Method and apparatus for improved heat controlled administration of pharmaceuticals

ABSTRACT

The present invention features methods and apparatus&#39;for improving administration of drugs through the use of specifically controlled heat and other physical means. The present invention relates to the use of heat and other physical means in conjunction with specially designed dermal drug delivery systems, conventional commercial dermal drug delivery systems, or drugs delivered into a sub-skin depot site via injection and other methods to alter, mainly increase, the drug release rate from the dermal drug delivery systems or the depot sites to accommodate certain clinical needs.

RELATED APPLICATIONS

This application is a divisional application claiming priority to U.S.application Ser. No. 09/544,897 filed Apr. 7, 2000, now U.S. Pat. No.6,613,350 and entitled, “Electrical Apparatus for Heating to a DesiredTemperature for Improved Administration of Pharmaceutically ActiveCompounds,” which is a divisional of U.S. application Ser. No.09/162,890 filed Sep. 29, 1998, and entitled, “Methods and apparatus forimproved administration of pharmaceutically active compounds” (now U.S.Pat. No. 6,245,347), which is a continuation-in-part of U.S. applicationSer. No. 08/819,880 filed Mar. 18, 1997, and entitled, “Noninvasivedermal anesthetics” (now U.S. Pat. No. 5,919,479), which is a divisionof U.S. application Ser. No. 08/508,463 filed Jul. 28, 1995, andentitled, “Apparatus and methods for improved noninvasive dermaladministration of pharmaceuticals” (now U.S. Pat. No. 5,658,583), eachincorporated by reference herein.

BACKGROUND

1. Field of the Invention

The present invention relates to methods and apparatus foradministration of drugs. More particularly, the present inventionrelates to using controlled heat and other physical means to improvedermal, mucosal, and injection administration of drugs.

2. Background of the Invention and Related Art

The dermal administration of pharmaceutically active compounds involvesthe direct application of a pharmaceutically active formulation(s) tothe skin, wherein the skin absorbs a portion of the pharmaceuticallyactive compound which is then taken up by the blood stream. Suchadministration has long been known in the practice of medicine andcontinues to be an important technique in the delivery ofpharmaceutically active compounds. For example, U.S. Pat. No. 4,286,592issued Sep. 1, 1981 to Chandrasekaran shows a bandage for administeringdrugs to a user's skin consisting of an impermeable backing layer, adrug reservoir layer composed of a drug and a carrier, and a contactadhesive layer by which the bandage is affixed to the skin.

Such dermal administration offers many important advantages over otherdelivery techniques, such as injection, oral tablets and capsules. Theseadvantages include being noninvasive (thus, less risk of infection),avoiding first pass metabolism (metabolism of the drug in the liver whenthe drug is taken orally and absorbed through the gastrointestinaltract), and avoiding of high peaks and low valleys of concentration ofpharmaceutically active compounds in a patient's bloodstream. Inparticular, high peaks and low valleys of concentration are typical ininjection and oral administrations and are often associated withundesirable side effects and/or less than satisfactory intended effects.

The term “dermal drug delivery system” or “DDDS”, as used herein, isdefined as an article or apparatus containing pharmaceutically activecompound(s) for delivery into the skin, the regional tissues under theskin, the systemic circulation, or other targeting site(s) in a humanbody via skin permeation. The term “DDDS” in this application, unlessotherwise specified, only refer to those systems in which the maindriving force for drug permeation is the drug concentration gradient.

The term “skin”, as used herein, is defined to include stratum comeumcovered skin and mucosal membranes.

The term “drug”, as used herein, is defined to include anypharmaceutically active compound including but not limited to compoundsthat treat diseases, injuries, undesirable symptoms, and improve ormaintain health.

The terms “targeted area” or “targeted areas”, as used herein, aredefined to include a systemic bloodstream of a human body, areas of ahuman body which can be reached by a systemic bloodstream including, butnot limited to muscles, brain, liver, kidneys, etc., and body tissueregions proximate a location of an administered drug.

In DDDSs, a drug(s) is usually contained in a formulation, such as ahydro-alcohol gel, and may include a rate limiting membrane between theformulation and skin for minimizing the variation in the permeation ofthe drug. When a DDDS is applied to skin, the drug begins to transportout of the formulation, and transport across the rate limiting membrane(if present). The drug then enters the skin, enters blood vessels andtissues under the skin, and is taken into the systemic circulation ofthe body by the blood. At least some DDDSs have certain amount ofpharmaceutically active compound in or on the skin side of the ratelimiting membrane (if present) prior to use. In those DDDSs, thatportion of the drug on the skin side of the rate limiting membrane willenter the skin without passing through the rate limiting membrane. Formany drugs, a significant portion of the dermally absorbed drug isstored in the skin and/or tissues under the skin (hereinafter referredas “depot sites”) before being gradually taken into the systemiccirculation (hereinafter referred as “depot effect”). This depot effectis believed to be at least partially responsible for the delayedappearance of the drug in the systemic circulation after the applicationof some DDDSs and for continued delivery of the drug into the systemiccirculation after the removal of some DDDSs from the skin.

After placing a DDDS on the skin, the drug concentration in the bloodtypically remains at or near zero for a period of time, before startingto gradually increase and reach a concentration deemed to be medicinallybeneficial, called the “therapeutic level” (the time it takes to reachthe therapeutic level is referred to hereinafter as the “onset time”).Ideally, the concentration of the drug in the bloodstream should plateau(i.e., reach a substantially steady state) at a level slightly higherthan the therapeutic level and should remain there for extended periodof time. For a given person and a given DDDS, the “concentration of thedrug in the bloodstream vs. time” relationship usually cannot be alteredunder normal application conditions.

The onset time and the delivery rate of the drug into the targetedarea(s) of the body for a typical DDDS are usually determined by severalfactors, including: the rate of release of the drug from theformulation, the permeability of the drug across the rate limitingmembrane (if a rate limiting membrane is utilized), the permeability ofthe drug across the skin (especially the stratum comeum layer), drugstorage in and release from the depot sites, the permeability of thewalls of the blood vessels, and the circulation of blood and other bodyfluid in the tissues (including the skin) under and around the DDDS.Although these primary factors affecting onset time and delivery rateare known, no existing DDDS is designed to have alterable delivery ratein the course of the application of the drug.

While a DDDS works well in many aspects, current dermal drug deliverytechnology has some serious limitations, including: 1) the onset timebeing undesirably long for many DDDSs; 2) the rate that the drug istaken into the systemic circulation or the targeted area(s) of the bodycannot be easily varied once the DDDS is applied onto the skin and, whenthe steady state delivery rate is achieved, it cannot be easily changed;and 3) the skin permeability being so low that many drugs are excludedfrom dermal delivery because the amount of drug delivered is not highenough to reach a therapeutic level. In addition, temperature variationsin the skin and the DDDS are believed contribute to the variation ofdermnal absorption of drugs.

It is known that elevated temperature can increase the absorption ofdrugs through the skin. U.S. Pat. No. 4,898,592, issued Feb. 6, 1990 toLatzke et al., relates to a device for the application of heatedtransdermally absorbable active substances which includes a carrierimpregnated with a transdermally absorbable active substance and asupport. The support is a laminate made up of one or more polymericlayers and optionally includes a heat conductive element. This heatconductive element is used for distribution of the patient's body heatsuch that absorption of the active substance is enhanced. U.S. Pat. No.4,230,105, issued Oct. 28, 1980 to Harwood, discloses a bandage with adrug and a heat-generating substance, preferably intermixed, to enhancethe rate of absorption of the drug by a user's skin. Separate drug andheat-generating substance layers are also disclosed. U.S. Pat. No.4,685,911, issued Aug. 11, 1987 to Konno et al., discloses a skin patchincluding a drug component, and an optional heating element for meltingthe drug-containing formulation if body temperature is inadequate to doso.

Another area of administration involves delivering drugs incontrolled/extended release form/formulations (“form/formulation”) intothe skin or tissues under the skin (the residing place for theseform/formulations are hereinafter referred as “storage sites”) whichresults in the drugs being released from the storage sites in acontrolled/extended fashion. The most common technique to deliver theform/formulations into the storage sites is by injection. Othertechniques may also be used, such as implantation and forcing theform/formulation into the skin with high-speed hitting. However, oncethe form/formulation is delivered into the storage sites, it is usuallydifficult to alter the rate, known as the “release rate”, that the drugis released from the form/formulation at the storage sites, and takeninto the systemic circulation or the targeted area(s) of the body.

Yet another area of administration involves injecting drugssubcutaneously or intramuscularly. In some clinical situations, it isbeneficial to accelerate the speed of drug absorption into the systemiccirculation or other targeted areas(s) in the body after such injection.

Therefore, it would be advantageous to develop methods and apparatus toimprove the drug administration of DDDSs, and, more specifically, tomake the use of DDDSs more flexible, controllable, and titratable(varying the drug delivery rate, amount, or period according to thebiological effect of the drug) to better accommodate various clinicalneeds. It would also be advantageous to develop methods and apparatus tomake dermal delivery possible for drugs which are currently excludedbecause of low skin permeability. It would further be advantageous todevelop means to alter mainly to increase the drug absorption rate fromthe storage sites or injection sites in such ways that can accommodatecertain clinical needs.

SUMMARY AND OBJECTS OF THE INVENTION

The present invention relates to various methods and apparatus forimproved dermal and mucosal administration of drugs through the use ofcontrolled heat and other physical means. The present invention furtherrelates to methods and apparatus for using controlled heat and otherphysical means to alter, mainly increase, the drug release rate from thestorage sites or injection sites in such ways to accommodate certainclinical needs.

In the application of a DDDS, the absorption of the drug is usuallydetermined by a number of factors including: the diffusion coefficientof drug molecules in the drug formulation, the permeability coefficientof the drug across the rate limiting membrane (if one is used in theDDDS), the concentration of dissolved drug in the formulation, the skinpermeability of the drug, drug storage in and release from the depotsites, the body fluid (including blood) circulation in the skin and/orother tissues under the skin, and permeability of the walls of capillaryblood vessels in the sub-skin tissues. Thus, in order to address thelimitations of the current dermal drug delivery technologies, it isdesirable to have control over and have the capability to alter thesedrug absorption factors. It is believed that controlled heating/coolingcan potentially affect each one of the above factors.

Specifically, increased temperature generally can increase diffusioncoefficients of the drugs in the formulations and their permeabilityacross the rate limiting membrane and skin. Increased heat alsoincreases the blood and/or other body fluid flow in the tissues underthe DDDS, which should carry the drug molecules into the systemiccirculation at faster rates. Additionally, increased temperature alsoincreases the permeability of the walls of the capillary blood vesselsin the sub-skin tissues. Furthermore, increased temperature can increasethe solubility of most, if not all, drugs in their formulations which,in formulations with undissolved drugs, should increase permeationdriving force. Of course, cooling should have substantially the oppositeeffect. Thus, the present invention uses controlled heating/cooling toaffect each of the above factors for obtaining controllable dermalabsorption of drugs.

The present invention also uses controlled heating/cooling in severalnovel ways to make dermal drug delivery more flexible and morecontrollable in order to deal with various clinical conditions and tomeet the needs of individual patients. More broadly, this inventionprovides novel methods and apparatus for controlled heating/cooling(hereinafter “temperature control apparatus”) during the application ofthe DDDS, such that heating can be initiated, reduced, increased, andstopped to accommodate the needs.

Another embodiment of the present invention is to determine the durationof controlled heating on DDDS based on the effect of the drug forobtaining adequate amount of the extra drug and minimizingunder-treatment and side effects associated with under and over dosing.

Through the proper selection, based on the specific application and/orthe individual patient's need, of the moment(s) to initiate controlledheating, heating temperature, and moment(s) to stop the controlledheating, the following control/manipulation of the absorption ratesshould be achieved: 1) shorten the onset time of the drug in the DDDSwithout significantly changing its steady state delivery rates; 2)provide proper amount of extra drug during the application of a DDDSwhen needed; and 3) increase the drug absorption rate throughout asignificant period of duration or throughout the entire duration of theDDDS application.

Shortening of onset time is important in situations where the DDDSprovides adequate steady state deliver rates, but the onset is too slow.Providing the proper amount of extra drug is important where a DDDSdelivers adequate “baseline” amount of the drug, but the patient needsextra drug at particular moment(s) for particular period(s) of timeduring the application of the DDDS. Increasing the drug absorption rateis used for the patients who need higher drug delivery rates from theDDDS.

The first of above approach can be achieved by applying controlledheating at the starting time of the DDDS application, and design theheating to last long enough to cause the concentration of the drug inthe systemic circulation or other targeted area of the body to risetoward the therapeutic levels, and stops (may be gradually) shortlyafter that. The second approach may be achieved by applying controlledheat when a need to obtain extra drug are rises, and terminating thecontrolled heating either at a predetermined moment or when the desiredeffect of the extra drug is achieved. The third approach can be achievedby applying the controlled heat at the starting time of the DDDSapplication. In all those three approaches, temperature of thecontrolled heating needs to be designed to control the degree ofincrease in said that drug delivery rates.

Such embodiments are particularly useful in situations where the user ofa DDDS gets adequate drug absorption most of the time, but there areperiods of time in which increased or decreased drug absorption isdesirable. For example, during the treatment of cancer patients with ananalgesic, such as with Duragesic.RTM. dermal fentanyl patches(distributed by Janssen Pharmaceutica, Inc. of Piscataway, N.J.,U.S.A.), “breakthrough” pain (a suddenly increased and relatively shortlasting pain, in addition to a continuous “baseline” pain) may occur. Anadditional analgesic dose, in the form of a tablet, an oral or nasalmucosal absorption dosage form, or an injection needs to be given totreat the breakthrough pain. But with the help of controlled heat, onesingle DDDS may take care of both baseline pain and episodes ofbreakthrough pain. With the help of controlled heat, a heating patch canbe placed on top of the Duragesic.RTM. patch when an episode ofbreakthrough pain occurs to deliver more fentanyl into the systemiccirculation. The heating duration of the heating patch is preferablydesigned to be long enough to deliver sufficient extra fentanyl, but notlong enough to deliver the extra amount of fentanyl that may pose a riskto the patient. The patient may also remove the heating patch when thebreakthrough pain begins to diminish. Thus, with the help of controlledheat, one single Duragesic.RTM. dermal fentanyl patch may take care ofboth baseline pain and episodes of breakthrough pain. For anotherexample, a dermal nicotine patch user may obtain extra nicotine for asuddenly increased nicotine craving by heating the nicotine patch.

Due to low skin permeability of the skin, onset times of conventionalDDDSs are usually quite long, and often undesirably long. Thus, anotheraspect of the present invention is to provide methods and apparatus forusing controlled heat to shorten the onset times of DDDSs, preferablywithout substantially changing the steady state drug delivery rates. Aparticularly useful application of this aspect of the present inventionis to provide a controlled heating apparatus for use with conventional,commercially available DDDSs to shorten the onset times in clinical use,without having to re-design the DDDSs or adjust their steady state drugdelivery rates.

It is believed that an important cause for variation in drug absorptionin DDDSs is variation in temperature of the DDDSs and the adjacent skincaused by variations in ambient temperature and/or physical condition ofthe person. This temperature variation can, of course, potentiallyaffect all of the factors that collectively determine the ultimate drugdelivery rates of the DDDSs. Thus, the present invention of providingmethods and apparatus to use controlled heating/cooling also minimizesthe variation in temperature of the skin and the DDDSs applied on theskin. It is also contemplated that an insulating material can beincorporated with the controlled temperature apparatus to assist in notonly minimizing the temperature variation, but also increasing thetemperature of the DDDS and the skin under it (by decreasing heat loss),each of which tend to increase dermal drug absorption.

The present invention also relates to methods and apparatus for using aninsulating device, such as a cover made of insulating material (such asclosed-cell foam tape) with adhesive edges, and a size slightly largerthan the DDDS or the area over an injected drug, to cover theDDDS/injected drug when the DDDS and/or the skin of the user is exposedto extreme temperature (such as a hot shower or bath, direct sunlight,etc.).

An important area in modern anesthesiology is patient controlledanalgesia (hereinafter “PCA”), in which the patient gives himself a doseof analgesic when he feels the need. The ranges of the dose and dosingfrequency are usually set by a care giver (i.e., caring physician,nurse, etc.). In many PCA situations, the patient receives a baselinerate of analgesic, and gets extra bolus analgesic when he feels that itis needed. The technology in the present invention may be used for a PCAin which the patient gets the baseline dose by a regular dermalanalgesic patch and the extra (“rescue”) dose by heating the dermalanalgesic patch. The heating temperature and duration needs to bedesigned to deliver a proper amount of extra dose.

Drugs in controlled or extended release forms or formulations may bedelivered into depot/storage sites in the skin and/or the tissues underthe skin with methods such as injection, implantation, hitting thedrug/drug formulation on the skin with supersonic speed, and embeddingthe drug/drug formulation onto the skin. The controlled/extendedform/formulation allows the drug to be released gradually into thesurrounding tissues and/or systemic circulation over an extended periodof time. For instance, extended release insulin (such as Ultralente.RTM.zinc insulin—Eli Lilly and Co.) can be injected subcutaneously todeliver insulin into the patient's systemic circulation over an extendedperiod of time. However, once the drug in the controlled/extendedform/formulation is delivered to the storage sites, it is usuallydifficult to alter or control the course of drug release. The apparatusand methods of the present invention allow controlled heat to increaseand controlled cooling to decrease, the drug release from thecontrolled/extended form/formulation after it is delivered into thedepot/storage sites. For example, many diabetic patients need additionalinsulin shortly before meals to suppress the blood sugar increaseresulting from the meals. However, the release rate of thesubcutaneously injected extended release insulin is relatively constant.With the methods and apparatus in the invention, a diabetic patient mayinject a subcutaneous extended release insulin in the morning and applycontrolled heat on the skin of the injection site for a duration of timeshortly before ingestion of a meal to obtain additional insulin tosuppress the sugar from the meal. The controlled heat increases the flowof blood and other body fluid surrounding the storage sites and isbelieved to increase the dissolution rate of insulin. It is, of course,understood that whether a given controlled/extended release formulationin the depot/storage sites can actually release extra drug withincreased temperature depends on the nature of the drugform/formulation. However, since heat is known or expected to increasethe diffusion speed of drugs in their formulations, increase thepermeability of blood vessel walls, and increases the circulation ofbody fluid surrounding the depot sites, each of which tend to favorincreased drug release, the heat-induced extra drug release is expectedto take place for many, if not most, controlled/extended drugform/formulation delivered into sub-skin storage sites.

One important aspect of the present invention is to properly choose thetemperature of the controlled heat and the moment(s) to initiate andstop the controlled heat in the applications with injected drugformulations, especially extended/controlled release formulations, toaccommodate the needs of different therapies and individual patients, inways similar to the applications with DDDSs discussed above.

Many biodegradable polymers may be used to make controlled/extendedrelease formulations. Of particular note are the biogradablelactic/glycolic acid polymers described in Chapters 29 and 33 ofEncyclopedic Handbook of Biomaterials and Bioengineering, edited byDonald L. Wise, et al., publ. Marcel Dekker, 1995, hereby incorporatedherein by reference. It is one important aspect of the present inventionto use controlled heat, as discussed above, to control/regulate drugrelease rates from controlled/extended release formulations made withsuch polymers, and preferably, prepared using the methods described inthe Encyclopedic Handbook of Biomaterials and Bioengineering.

For drugs where quick systemic absorption is important, the presentinvention may be beneficial. For example, it is generally agreed that tosuccessfuilly treat a migraine headache, concentrations of ananti-migraine drug, such as dihydroergotamine, in the bloodstream mustreach a therapeutic level within a certain time from the onset ofmigraine headache. In such situations, the heating devices, as discussedabove, may be used with normal injection of drugs. Since heat canusually increase the diffusion speed of drugs in their formulations,increase the permeability of blood vessel walls, and increases thecirculation of body fluid surrounding the injection site, the drug willenter the system circulation more quickly.

One of the more important aspects of the present invention is theapparatus for generating and providing controlled heating. Thesecontrolled heat generating apparatus generally comprise a heatgenerating portion and a means to pass the heat generated by the heatgenerating portion to the DDDSs, the skin, and/or the sub-skin depot andstorage sites. These controlled heat generating apparatus generallyfurther include a mechanism (such as tape, adhesive, and the like) foraffixing apparatus onto the DDDSs and/or the skin. Preferably, theaffixation mechanism securely holds the controlled heat generatingapparatus in place while in use, but it also allows relatively easyremoval after use. Additionally, these controlled heat generatingapparatus may further include a mechanism for terminating the generationof heat. The shape and size of the bottom of the controlled heatgenerating apparatus are generally specially made to accommodate theDDDSs with which they are to be employed.

One embodiment of a controlled heat generating apparatus is a shallowchamber including non-air permeable side wall(s), a bottom wall, and anon-air permeable top wall which has area(s) with limited and desiredair permeability (e.g., holes covered with a microporous membrane). Aheat generating medium is disposed within the shallow chamber. The heatgenerating medium preferably comprises a mixture of iron powder,activated carbon, salt, water, and, optionally, sawdust. The controlledheat generating apparatus is preferably stored in an air-tight containerfrom which it is removed prior to use. After removal from the air-tightcontainer, oxygen in the atmosphere (“ambient oxygen”) flows into heatgenerating medium through the areas on the non-air permeable top withdesired air-permeability to initiate a heat generating oxidationreaction (i.e., an exothermic reaction). The desired heating temperatureand duration can be obtained by selecting the air exposure of the top(e.g., selecting the right size and number of holes on the cover-and/orselecting the microporous membrane covering the holes for a specific airpermeability), and/or by selecting the right quantities and/or ratios ofcomponents of the heat generating medium.

This embodiment of the controlled heat generating apparatus preferablyincludes a mechanism for affixing the controlled heat generatingapparatus onto the skin or a DDDS that is applied to the skin. Forapplications where the removal or termination of the heating might benecessary, the heat generating apparatus may also have a mechanism forallowing easy removal from the DDDS and/or the skin or for terminationof the heating. One mechanism for allowing easy removal of the shallowchamber from a DDDS without removing the latter from the skin comprisesa layer of adhesive on the side walls of the heat generating apparatuswith an non-adhesive area or less adhesive area (less adhesive than theadhesive affixing the DDDS to the skin) at the bottom of the shallowchamber, with the non- or less adhesive area having a shape similar tothat of the DDDS. When such a heat generating apparatus is applied ontothe DDDS which is on the skin, the adhesive at the bottom of the sidewalls of the heat generating apparatus adheres to the skin, and non- orless adhesive part is on top of, but not adhered or not strongly adheredto, the DDDS. This allows for removal of the heat generating apparatuswithout disturbing the DDDS.

Although one application of such a heat generating apparatus is to beused in conjunction with a DDDS, it is understood that the heatgenerating apparatus can also be applied directly to the skin toincrease the release of drugs from depot sites or sites of injection orimplantation of controlled released drugs (storage sites), or toaccelerate the absorption of subcutaneously or intramuscularly injecteddrugs.

The heat generating mechanism of the present invention for thecontrolled heat generating apparatus is not limited to the preferredexothermic reaction mixture of iron powder, activated carbon, salt,water, and, optionally, sawdust, but may include a heating unit whoseheat is generated by electricity. The electric heating unit, preferably,includes a two dimensional surface to pass the heat to the DDDS and/orthe skin. The electric heating unit may also include a temperaturefeedback system and a temperature sensor that can be placed on the DDDSor the skin. The temperature sensor monitors the temperature at the DDDSor skin and transmits an electric signal based on the sensed temperatureto a controller which regulates the electric current or voltage to theelectric heating unit to keep the temperature at the DDDS or skin atdesired levels. Preferably, a double sided adhesive tape can be used toaffix the electric heating unit onto the skin.

The heat generating mechanism may also comprise an infrared generatingunit and a mechanism to direct the infrared radiation onto the DDDS orthe skin. It may also have a temperature feedback system and atemperature sensor that can be placed on the DDDS or the skin to controlthe intensity of the infrared emission to maintain the temperature atthe DDDS or skin at desired levels.

The heat generating mechanism may further comprise a microwavegeneration unit and a mechanism to direct the microwave radiation ontothe DDDS or the skin. Again, the heat generating mechanism may have atemperature feedback system and a temperature sensor to regulate theintensity of the microwave emission to maintain the temperature at theDDDS or skin at desired levels.

The heat generating mechanism may yet further comprise a containercontaining supercooled liquid which generates heat from crystallization(“exothermic”). The crystallization is initiated within the container,such as by bending a metal piece in the supercooled liquid, and thecontainer is placed on a DDDS or on the skin. The heat which is releasedfrom the crystallization process is passed to the DDDS and/or the skin.However, heat generated by crystallization usually does not maintain aconstant level over extended time. Thus, such a heat generatingmechanism is not ideal for applications where elevated temperature in anarrow range over an extended time is necessary, but is useful whereonly a short heating duration is needed, such as with a DDDS that wouldbenefit from short heating duration to minimize the onset time.

Although, in general, most benefits for DDDSs are realized fromincreased drug absorption and release rates by heating, there arecircumstances where it may be desirable to be able to both increase anddecrease the drug absorption and release rates. It is understood thatfor a more complete control in dermal and controlled/extended releasedrug administration that a mechanism for providing both heating orcooling, depending on need, would be advantageous. Thus, a novelapproach of this invention is to provide methods and apparatus forproviding heating or cooling to the DDDSs, the skin and/or the tissuesunder it, or the controlled/extended release drug form/formulation inthe skin or the tissues under the skin, such that the drug absorptionand/or release can be controlled. The heating/cooling mechanismcomprises a thermoelectric module which functions as a heat pump whereinthe power supply may be reversed depending on whether heating or coolingis desired. A cooling mechanism can include an endothermiccrystallization mechanism similar to the exothermic crystallizationmechanism discussed above.

It is, of course, understood that the use of controlled heating and/orcooling to control drug absorption and/or release are equally applicableto controlled/extended form/formulations after they are delivered intothe skin and/or tissues under the skin. However, physical mechanismsother than heating and/or cooling may also be used for the same purpose.Thus, it is novel approach of this invention to provide methods andapparatus to use ultrasound, electric current, and mechanical vibrationto induce extra drug release from controlled/extended releaseform/formulations which are already delivered into the body and that areresponsive to these physical induction means.

BRIEF DESCRIPTION OF THE DRAWINGS

In order that the manner in which the above-recited and other advantagesand features of the invention are obtained, a more particulardescription of the invention briefly described above will be rendered byreference to specific embodiments thereof which are illustrated in theappended drawings. Understanding that these drawings depict only typicalembodiments of the invention and are not therefore to be consideredlimiting of its scope, the invention will be described and explainedwith additional specificity and detail through the use of theaccompanying drawings in which:

FIG. 1 is a side cross-sectional view of an embodiment of a temperaturecontrol apparatus according to the present invention;

FIG. 2 is a side cross-sectional view of another embodiment of atemperature control apparatus according to the present invention;

FIG. 3 is a side cross-sectional view of an embodiment of a dermal drugdelivery system according to the present invention;

FIG. 4 is a side cross-sectional view of the temperature controlapparatus of FIG. 2 in conjunction with the dermal drug delivery systemof FIG. 3 according to the present invention;

FIG. 5 is a graph of time versus temperature for a temperature controlapparatus according to the present invention;

FIG. 6 is a graph of the mean fentanyl concentration of nine volunteersverse time for a four hour contact of a fentanyl containing DDDS withheating and without heating according to the present invention;

FIG. 7 is a graph of time versus temperature for a temperature controlapparatus according to the present invention;

FIG. 8 is a side cross-sectional view of another embodiment of atemperature control apparatus according to the present invention;

FIG. 9 is a side cross-sectional view of another embodiment of a dermaldrug delivery system according to the present invention;

FIG. 10 is a side cross-sectional view of the temperature controlapparatus of FIG. 8 in conjunction with the dermal drug delivery systemof FIG. 9 according to the present invention;

FIG. 11 is a side cross-sectional view of still another embodiment of adermal drug delivery system according to the present invention;

FIG. 12 is a side cross-sectional view of the temperature controlapparatus of FIG. 8 in conjunction with the dermal drug delivery systemof FIG. 11 according to the present invention;

FIG. 13 is a side cross-sectional view of yet another embodiment of atemperature control apparatus having three cover layers over an oxygenactivated temperature regulating mechanism chambers according to thepresent invention;

FIG. 14 is a side cross-sectional view of the temperature controlapparatus of FIG. 13 having a first cover layer removed according to thepresent invention;

FIG. 15 is a top plan view of the temperature control apparatus of FIG.14 along line 15-15 according to the present invention;

FIG. 16 is a side cross-sectional view of the temperature controlapparatus of FIG. 14 having a second cover layer removed according tothe present invention;

FIG. 17 is a top plan view of the temperature control apparatus of FIG.16 along line 17-17 according to the present invention;

FIG. 18 is a side cross-sectional view of the temperature controlapparatus of FIG. 16 having a third cover layer removed according to thepresent invention;

FIG. 19 is a top plan view of the temperature control apparatus of FIG.18 along line 19-19 according to the present invention;

FIG. 20 is a side cross-sectional view of another embodiment of a dermaldrug delivery system having a rate limiting membrane according to thepresent invention;

FIG. 21 is a side cross-sectional view of an electric temperaturecontrol mechanism according to the present invention;

FIG. 22 is a side cross-sectional view of a temperature controlapparatus comprising a flexible bag filled with a supercooled liquidaccording to the present invention;

FIG. 23 is a side cross-sectional view of a temperature controlapparatus capable of both heating and cooling applied to a DDDSaccording to the present invention;

FIG. 24 is a schematic for a closed loop temperature controller for thetemperature control apparatus of FIG. 23 according to the presentinvention;

FIG. 25 is a side cross-sectional view of a temperature controlapparatus applied directly to a patient's skin according to the presentinvention;

FIG. 26 is a side cross-sectional view an electrical mechanism forincreasing drug absorption according to the present invention;

FIG. 27 is a side cross-sectional view a vibrational mechanism forincreasing drug absorption according to the present invention;

FIG. 28 is a side cross-sectional view of a temperature controlapparatus capable of both heating and cooling applied directly to apatient's skin according to the present invention; and

FIGS. 29-32 is a side cross-sectional view an insulative material over aDDDS and injected or depot drug sites for minimizing temperaturevariation and/or increasing the temperature of the DDDS and the skinthereunder according to the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

It will be readily understood that the components of the presentinvention, as generally described and illustrated in the figures herein,could be arranged and designed in a wide variety of differentconfigurations. Thus, the following more detailed description of theembodiments of the system and method of the present invention, andrepresented in FIGS. 1 through 32, is not intended to limit the scope ofthe invention, as claimed, but is merely representative of the presentlypreferred embodiments of the invention.

The presently preferred embodiments of the invention will be bestunderstood by reference to the drawings wherein like parts aredesignated by like numerals throughout.

FIGS. 1-32 illustrate various views of temperature control or otherapparatuses and dermal drug delivery systems. It should be understoodthat the figures presented in conjunction with this description are notmeant to be illustrative of actual views of any particular apparatus,but are merely idealized representations which are employed to moreclearly and fully depict the present invention than would otherwise bepossible. Elements common between the figures retain the same numericdesignations.

FIG. 1 illustrates a temperature control apparatus 100 of the presentinvention comprising a chamber defined by a bottom wall 102, a top wall104, and side walls 106 wherein a temperature regulating mechanism 108is disposed within the chamber. The temperature regulating mechanism 108can include a heat generating oxidation reaction mechanism, electricheating unit, exothermic crystallization mechanism, endothermiccrystallization mechanism, heating/cooling mechanism, cooling mechanism,or the like.

FIG. 2 illustrates a temperature control apparatus 100 comprising atemperature regulating mechanism 108 surrounded by a bottom wall 102, atop wall 104, and side walls 106. The bottom wall 102 is preferably aplastic material and the side walls 106 are preferably made of aflexible non-air permeable material, such as non-air permeableclosed-cell foam material. A portion or all of the bottom wall 102 ofthe temperature control apparatus 100 includes an adhesive material 112for attachment to a DDDS or to the skin of a patient. The temperatureregulating mechanism 108 preferably comprises a composition of activatedcarbon, iron powder, sodium chloride and water in a proper ratio.Optionally, saw dust may be added to the composition to facilitate theairflow within the composition and/or provide “body” to the composition.The top wall 104 is preferably also a flexible non-air permeablematerial having holes 114 therethrough. An air permeable membrane 116is, preferably, disposed between the top wall 104 and the temperatureregulating mechanism 108 to regulate the amount of air reaching thetemperature regulating mechanism 108 through the holes 114. The airpermeable membrane 116 is preferably a porous film (such as No. 9711microporous polyethylene film—CoTran.TM., 3M Corporation, Minneapolis,Minn., U.S.A).

FIG. 3 illustrates a dermal drug delivery system 120 (hereinafter “DDDS120”) comprising a housing 122 made of a flexible material(s). Thehousing 122 preferably comprises side walls 124 and a top wall 126 witha drug formulation 128 disposed within the housing 122. Preferably, thebottom of the DDDS side walls 124 include an adhesive 132 to affix theDDDS 120 to the skin of a patient.

FIG. 4 illustrates the temperature control apparatus 100 of FIG. 2attached to the DDDS 120 of FIG. 3. The DDDS 120 attached to a portionof the skin 134 of a patient. The area of the temperature regulatingmechanism 108 is preferably slightly larger than that of the drugformulation 128. The temperature control apparatus 100 and the DDDS 120are preferably stored in separated compartments of an air tightcontainer (or in separate air tight containers).

EXAMPLE 1

One example of using the embodiment of the present invention illustratedin FIGS. 2-4 for administering analgesic material for relief of painconsists of a patient or care giver placing the DDDS 120 on the skin 134of the patient, which preferably adheres to the skin 134 with DDDSadhesive 132. The patient or care giver then attaches the temperaturecontrol apparatus 100 on top of the DDDS 120, which adheres to the DDDS120 with temperature control apparatus adhesive 112. Oxygen in ambientair flows into the temperature regulating mechanism 108 through holes114 and air permeable membrane 116. Of course, it is understood that therate at which oxygen contacts the temperature regulating mechanism 108is determined by the size and number of the holes 114 on the top wall104, as well as the air permeability of the air permeable membrane 116.A heat generating (exothermic) chemical reaction occurs in thetemperature regulating mechanism 108. Heat from this reaction passesthrough the temperature control apparatus bottom wall 102, through theDDDS top wall 126, through the drug formulation 128, and increases thetemperature of the patient's skin 134 under the DDDS 120.

In actual experimentation, the temperature control apparatus 100comprised the side walls 106 defined by a ⅛ inch thick rectangular foamtape (2 layers of No. 1779 {fraction (1/16)}″ white foam tape, 3MCorporation, Minneapolis, Minn., U.S.A) with an outer dimension of about2.25 inches by 4 inches with an opening therein having an innerdimension of about 1.75 inches by 3.5 inches, the bottom wall 102comprising rectangular medical tape (No. 1525L plastic medical tape, 3MCorporation, Minneapolis, Minn., U.S.A) of a dimension of about 2.25inches by 4 inches with a non-adhesive side attached to the bottom ofthe side walls 106, and a top wall 104 comprising a rectangular{fraction (1/32)} inch thick foam tape (No. 9773 {fraction (1/32)}″ tanfoam tape, 3M Corporation, Minneapolis, Minn., U.S.A) with forty-fiveholes 114 (diameters approximately 0.9 mm, in a 5 by 9 pattern withabout 7.5 mm to 8.0 mm center spacing) therethrough. The side walls 106,the bottom wall 102, and the top wall 104 defined a chamber. The holes114 of the top wall 104 were covered by an air permeable membrane 116comprising a porous membrane (No. 9711 microporous polyethylenefilm—CoTran.TM., 3M Corporation, Minneapolis, Minn., U.S.A) disposedbetween the top wall 104 and the temperature regulating mechanism 108.The side walls 106, the bottom wall 102, and the top wall 104 all had ⅛″rounded corners. The temperature regulating mechanism 108 disposed inthe chamber comprised a mixture of activated carbon (HDC grade—NoritAmericas, Inc., U.S.A), iron powder (grade R1430—ISP Technologies,U.S.A), saw dust (Wood Flour, Pine—Pioneer Sawdust, U.S.A), sodiumchloride and water in the weight ratio of approximately 5:16:3:2:6weighing approximately 16.5 grams. The temperature control apparatus 100was sealed in an air-tight container immediately after fabrication.

The temperature control apparatus 100 was tested on a volunteer with atemperature probe placed between the temperature control apparatus 100and the volunteer's skin to measure the temperature. The results of thistemperature experiment is illustrated in FIG. 5 and Table A, which showsthat the temperature control apparatus 100 is capable of keeping theskin temperature to a narrow, elevated range of about 41.degree. C. to43.degree. C. for extended period of time (at least about 240 minutes).

TABLE A Time (minutes) Temperature (.degree. C.) 0 30.6 1 31.8 2 33.6 335.2 4 36.6 5 38.0 6 39.1 7 39.9 8 40.5 9 41.1 10 41.5 11 41.9 12 42.313 42.5 14 42.5 15 42.5 16 42.5 17 42.5 18 42.5 19 42.5 20 42.5 22 42.424 42.4 26 42.3 28 42.2 30 42.5 35 42.5 40 42.6 45 42.6 60 42.5 75 42.890 42.7 120 42.6 150 42.3 180 42.0 210 41.8 240 41.0 255 40.4

Nine human volunteers receive a dose of fentanyl in a DDDS 120. The DDDS120 comprised a commercially available dermal fentanyl patch,Duragesic-50.RTM. (designed to deliver an average of 50 micrograms offentanyl per hour), distributed by Janssen Pharmaceutica, Inc. ofPiscataway, N.J., U.S.A. The experiment was conducted to determinefentanyl concentrations within the volunteers' blood (over a 12 hourperiod) without heating the DDDS 120 and with heating the DDDS 120 (withthe temperature control apparatus 100 described above). The experimentswere conducted with at least a two week time period between the heatedand unheated sessions. In the unheated session, the DDDS 120 was appliedonto the volunteer's chest skin and removed after about 240 minutes. Inthe heated session, the DDDS 120 was applied onto the subject's chestskin and immediately cover by the temperature control apparatus 100.Both the DDDS 120 and the temperature control apparatus 100 were removedafter about 240 minutes. In both sessions, blood samples were taken atvarious intervals for 12 hours and the fentanyl concentrations in serumsamples were determined by radioimmunoassay.

FIG. 6 and Table B illustrates the mean serum fentanyl concentrationsproduced by the heated and unheated Duragesic-50.RTM. patches,respectively, over a 720 minute duration (The lowest standard used inthe assay was 0.11 ng/ml. Concentrations lower than 0.11 ng/ml wereobtained using an extrapolation method.). With heating by thetemperature control apparatus 100, it was found that fentanyl began toenter the systemic circulation earlier, and at faster rates. At 240minutes, the end of the heating and fentanyl patch application, theaverage serum concentrations of fentanyl in the volunteers with theheating of the Duragesic-50.RTM. patch was about 5 times that of theunheated Duragesic-50.RTM. These results demonstrates that controlledheat can significantly increase the speed of dermal fentanyl absorptionand shorten the onset time.

TABLE B Serum Fentanyl Conc. Serum Fentanyl Conc. Without Heat With HeatTime (minutes) (ng/ml) (ng/ml) 0 0.04 0.01 10 0.03 0.01 20 0.03 0.02 300.03 0.03 40 0.03 0.06 60 0.04 0.09 75 0.03 0.16 90 0.04 0.28 120 0.060.45 180 0.14 0.85 240 0.26 1.29 300 0.47 1.04 360 0.40 0.98 420 0.330.88 480 0.35 0.67 540 0.38 0.63 600 0.37 0.51 660 0.33 0.50 720 0.260.49

Thus, it is believed that the increased temperature increases the skinpermeability (compared with a DDDS without such a heating mechanism),which results in the fentanyl entering, the patient's systemiccirculation faster. This should result in serum fentanyl concentrationsreaching steady state quicker. The heating is also believed to increasethe body fluid circulation and blood vessel wall permeability in thesub-skin tissues, and cause fentanyl to spend less time in the sub-skindepot site. As a result, the patient receives the analgesic compoundmore quickly and receives improved pain relief.

In yet another experiment, the temperature control apparatus 100comprised the side walls 106 defined by a {fraction (3/16)} inch thickrectangular foam tape (3 layers of No. 1779 {fraction (1/16)}″ whitefoam tape, 3M Corporation, Minneapolis, Minn., U.S.A) with an outerdimension of about 2.25 inches by 4 inches with an opening thereinhaving an inner dimension of about 1.75 inches by 3.5 inches, the bottomwall 102 comprising rectangular medical tape (No. 1525L plastic medicaltape, 3M Corporation, Minneapolis, Minn., U.S.A) of a dimension of about2.25 inches by 4 inches with a non-adhesive side attached to the bottomof the side walls 106, and a top wall 104 comprising a rectangular{fraction (1/32)} inch thick foam tape (No. 9773 {fraction (1/32)}″ tanfoam tape, 3M Corporation, Minneapolis, Minn., U.S.A) with seventy-eightholes 114 therethrough (diameters approximately {fraction (1/32)} inch,in a 6 by 13 pattern with about a 6 mm center spacing). The side walls106, the bottom wall 102, and the top wall 104 define a chamber. Theholes 114 of the top wall 104 are covered by an air permeable membrane116 comprising a porous membrane (No. 9711 CoTran.TM. membrane, 3MCorporation, Minneapolis, Minn., U.S.A) disposed between the top wall104 and the temperature regulating mechanism 108. The side walls 106,the bottom wall 102, and the top wall 104 all had ⅛″ rounded corners.The temperature regulating mechanism 108 disposed in the chambercomprised a mixture of activated carbon, iron powder, saw dust, sodiumchloride and water in the weight ratio of approximately 5:16:3:2:6weighing approximately 25 grams. This temperature control apparatus 100was tested on a volunteer's stomach with a temperature probe placedbetween the temperature control apparatus 100 and the volunteer's skinto measure the temperature. The results of this temperature experimentis illustrated in FIG. 7 and Table C, which shows that the temperaturecontrol apparatus 100 is capable of keeping the skin temperature to anarrow, elevated range at between about 41 and 44.degree. C. forextended period of time (at least about 450 minutes).

TABLE C Time (minutes) Temperature (.degree. C.) 0 29.6 1 31.9 15 39.316 39.9 17 40.6 18 41.0 19 41.4 20 41.9 22 42.7 24 43.2 26 43.6 28 43.730 43.5 35 43.5 40 43.3 45 43.3 60 43.1 75 42.9 90 43.0 120 43.0 15043.2 180 43.0 210 42.6 240 42.5 270 42.3 300 43.0 330 43.0 360 42.6 39042.6 420 42.5 450 41.9

FIG. 8 illustrates another embodiment of a temperature control apparatus150 comprising a temperature regulating mechanism 108 surrounded by abottom wall 102, a top wall 104, and side walls 152. The side walls 152extend a distance below the bottom wall 102 to define a cavity 154. Thebottom wall 102 is preferably made of plastic tape material and the sidewalls 152 are preferably made of a flexible non-air permeable material,such as non-air permeable closed-cell foam material. A portion of thebottom of the temperature control apparatus 150 includes an adhesivematerial 112 on the bottom of the side walls 152 and, preferably,includes a second adhesive material 156 in the bottom of the bottom wall102, wherein the second adhesive material 156 is preferably lessadhesive than the adhesive material 112. Again, the temperatureregulating mechanism 108 preferably comprises a composition of activatedcarbon, iron powder, sodium chloride, water, and, optionally, saw dust.The top wall 104 is preferably also a flexible non-air permeablematerial having holes 114 therethrough. An air permeable membrane 116 isdisposed between the top wall 104 and the temperature regulatingmechanism 108 to regulate the amount of air reaching the temperatureregulating mechanism 108 through the holes 114.

FIG. 9 illustrates a DDDS 160 comprising a housing made 122 of flexiblematerials. The housing 122 preferably comprises side walls 124 and a topwall 126 with a drug formulation 128 disposed within the housing 122,and may include a membrane 130 which may be a rate-limiting membrane.

FIG. 10 illustrates the temperature control apparatus 150 of FIG. 8attached to the DDDS 160 of FIG. 9. The DDDS 160 is placed on (orattached with an adhesive, not shown) a portion of the skin 134 of apatient and the temperature control apparatus 150 is placed over theDDDS 160, such that the DDDS 160 resides within the cavity 154 (see FIG.8). The adhesive material 112 attaches to the skin 134 and holds thetemperature control apparatus 150 in place. If the DDDS 160 is notattached to the skin 134, the temperature control apparatus 150 holdsthe DDDS 160 in place. Preferably, the DDDS 160 is attached to the skin134 with an adhesive material (not shown) with the temperature controlapparatus 150 placed over the DDDS 160. The temperature controlapparatus 150 is attached to the skin 134 with the adhesive material 112and the second adhesive material 156 (less adhesive than any attachmentadhesive (not shown) between the DDDS 160 and the skin 134 and lessadhesive than the adhesive material 112 between the temperature controlapparatus 150 and the skin 134) attaches the temperature controlapparatus 150 to the DDDS 160. Such an arrangement results in secureadhesion of the temperature control apparatus 150 and the DDDS 160 tothe skin 134, yet allows for the removal of the temperature controlapparatus 150 without removing the DDDS 160.

FIG. 11 illustrates an alternate DDDS 165 comprising a housing 123 madeof flexible material(s). The housing 123 preferably comprises top wall125 and a membrane 103, which may be a rate-limiting membrane, with adrug formulation 128 disposed within the housing 123. FIG. 12illustrates the temperature control apparatus 150 of FIG. 8 attached tothe DDDS 165 of FIG. 11, similar that described for FIG. 10.

EXAMPLE 2

An example of using the embodiment of the present invention illustratedin FIGS. 8-12 for administering analgesic material to treat breakthroughpain consists of a patient or care giver placing the DDDS 160, 165 onthe skin 134 of the patient with the temperature control apparatus 150placed thereover. By way of example, when the DDDS 160, 165 is acommercially available fentanyl patch, Duragesic-50.RTM., it takesseveral hours after the application of the DDDS 160, 165 to obtain asufficient steady state level of fentanyl in the patient's bloodstreamto control baseline pain. However, such as with the treatment of cancerpatients, a patient will from time to time suffer breakthrough pain,which is a suddenly increased but usually not long lasting pain. When apatient feels that a breakthrough pain episode is imminent, the patientplaces the temperature control apparatus 150 over the DDDS 160, 165. Theheat from the temperature control apparatus 150 increases thetemperature of the fentanyl patch, the skin, and tissues under the skin.As a result, more fentanyl is absorbed across the skin. Furthermore,fentanyl already in the skin and sub-skin depot sites (i.e., fentanylmolecules that have already permeated across the skin but were stored inthe skin and sub-skin tissues) starts to be released into the systemiccirculation at faster rates because of increased blood/body fluid flowin the tissues under the fentanyl patch and increment blood vessel wallpermeability caused by heat from the temperature control apparatus 150.The overall result is that fentanyl concentration in the patient'sbloodstream is significantly increased shortly after the heating patchis applied (compared with no temperature control apparatus 150 beingused), and the increased fentanyl in the bloodstream alleviates thebreakthrough pain in a timely manner. It is believed that for lipophiliccompounds, such as fentanyl, that usually have significant dermal depoteffect (storage in depot sites in the skin and sub-skin tissues andgradual release from the depot sites), the increased drug release fromthe depot sites due to the heating may make a more rapid and a moresignificant contribution to increasing bloodstream drug concentrationsthan the contribution from increased skin permeability caused by theheat. The patient can leave the heating patch on for a pre-determinedlength of time, based on his previous experience of breakthrough pain,before he stops the heating by removing the patch or placing an airimpermeable tape to cover all the holes on the top wall 104. The patientmay also stop the heating when he feels the current episode ofbreakthrough pain is over or beginning to end.

Preferably, the heating patch is designed to have a predeterminedheating duration that is sufficient to treat most patients'breakthroughpain, but not long enough to cause serious side effects associated withfentanyl overdose. However, if a particular patient has a highertolerance to fentanyl, the patient can use two or more of the heatingpatches consecutively so that the patient gets just enough extrafentanyl to treat the breakthrough pain.

EXAMPLE 3

Another example of using the embodiment of the present inventionillustrated in FIGS. 8-12 for dermally administering nicotine forsuppressing nicotine craving consists of a user placing a nicotine DDDS160, 165 on the skin 134. After a few hours, the user should obtain asteady state nicotine concentration in the bloodstream that issufficient to suppress a “baseline” nicotine craving. When the userstarts to have an episode of increased nicotine craving, the user putsthe temperature control apparatus 150 on top of the DDDS 160, 165. Thetemperature control apparatus 150 preferably heats for at least 15minutes before the exothermic reaction exhausts the temperatureregulating mechanism 108. The heat increases the transport of nicotineacross the skin, and increases the blood flow in the tissues under theDDDS 160, 165 which carries nicotine stored in the tissues under theDDDS 160, 165 into the systemic circulation at increased rates. As aresult, the user gets a rapid increase in his blood nicotineconcentration to treat the surge of the nicotine craving. After theheating, the nicotine absorption rates gradually come back to normal todeliver the steady state nicotine concentration in the bloodstream.

EXAMPLE 4

Another example of using the embodiment of the present inventionillustrated in FIGS. 8-12 for dermally administering testosterone toincrease and optimize the amount of drug delivered consists of a userplacing the DDDS 160, 165, such as a once a day dermal testosteronepatch, for example Androderm.RTM. produced by Theratech, Inc. of SaltLake City, Utah, U.S.A, on the skin 134. The DDDS 160, 165 is generallyapplied to the skin 134 at night, for example at 10 PM. However, if theuser does not get a sufficient dosage of testosterone the next day, theuser puts the temperature control apparatus 150 on top of the DDDS 160,165. The increased temperature in the DDDS 160, 165, the skin 134 andtissues under the skin significantly increase the dermal absorption oftestosterone. In addition, if the DDDS 160, 165 has permeation enhancer,such as glycerol monooleate, the heat should also make the enhancerpermeate the skin faster, thus making it more effective. The ultimateresult is that the user gets sufficient testosterone from the DDDS 160,165. Furthermore, the user may also place the temperature controlapparatus 150 on the DDDS 160, 165 in the morning to deliver moretestosterone from morning to the evening when the user needs the higherdosage the most. The increased absorption of testosterone by thecontrolled heating may allow the readuction of a permeation enhancerconcentration which is used in the DDDS 160, 165. In a testosteroneDDDS, a permeation enhancer is usually necessary for deliveringsufficient testosterone, however permeation enhancers may cause seriousskin irritation, such as glycerol monooleate in Androderm.RTM.

EXAMPLE 5

It is, of course, understood that the DDDS 160, 165 and the temperaturecontrol apparatus 150 can be with athletic injuries. For example, if aperson injures an elbow in a sporting event or such, the user can applya DDDS 160, 165 containing an analgesic, such a dexamethasone,wintergreen oil, or the like, wherein the DDDS 160, 165. The heatgenerated by the temperature control apparatus 150 drives more drug intothe elbow and the increased the blood flow induced by the heat takes thedrug deeper into the elbow.

EXAMPLE 6

Yet another example of using the embodiment of the present inventionillustrated in FIGS. 8-12 comprises using the temperature controlapparatus 150 for administering analgesic material to treat pain whenthe diffusion coefficient of the active ingredients in the formulation128 and/or permeability coefficient across a rate limiting membrane 130is so low that it dominantly determines the overall absorption rate ofanalgesic material from the DDDS 160, 165 into a patient's body. By wayof example with the use of a DDDS 160, 165, the patient or care giverplaces the DDDS 160, 165 on the skin 134 of the patient. If after a timeof wearing the DDDS 160, 165, it is determined that for this particularpatient and his conditions a higher concentration of fentanyl in thebloodstream is required to properly treat his pain, the temperaturecontrol apparatus 150 is placed on top of the DDDS 160, 165 to heat theDDDS 160, 165.

The increased temperature increases diffusion coefficient of the activeingredient in the formulation in the DDDS 160, 165 and increases thepermeability coefficient across the rate limit membrane 130 in the DDDS160, 165, and, thus, the overall rates at which the active ingrediententers the patient's body. This, in turn, increases the concentration ofactive ingredient in the bloodstream. As a result, the patient gets theincreased and proper effect.

EXAMPLE 7

Still another example of using the embodiment of the present inventionillustrated in FIGS. 8-12 comprises using the temperature controlapparatus 150 for decreasing onset time of an analgesic material fromthe DDDS 160, 165. By way of example with the use of a commerciallyavailable fentanyl patch, such as Duragesic-50.RTM., as the DDDS 160,165, the patient or care giver places the DDDS 160, 165 on the skin 134of the patient and places the temperature control apparatus 150 over theDDDS 160. Preferably, the temperature control apparatus 150 includes asufficient amount of activated carbon, iron powder, sodium chloride, andwater in the temperature regulating mechanism 108 to sustain anexothermic reaction for at least 4 hours.

The heat from the temperature control apparatus 150 increases thetemperature at a contact surface of the skin 134 and the DDDS 160, 165to temperatures up to about 60.degree. C., preferably a narrowtemperature range between about 36.degree. C. and 46.degree. C., mostpreferably between 37.degree. C. and 44.degree. C., and maintains thistemperature for a period of time (i.e., approximately 4 hours). Duringthis time, the heat increases the speed of fentanyl release from theDDDS 160, 165, the permeation rate across the skin 134, and the speed ofblood circulation which carriers the fentanyl into the systemiccirculation faster. After the exothermic reaction ceases (approximately4 hours), the fentanyl absorption and concentration in the bloodstreambegins to decrease from the elevated levels caused by the heat from theDDDS 160, 165 returns to normal (unheated) levels. The patient continuesto wear the system for a total of between about 48 and 72 hours.Compared with a DDDS 160, 165 without the use of the temperature controlapparatus 150, the fentanyl begins to appear in the bloodstreamsignificantly earlier to yield a shortened onset time and the fentanylconcentrations in the bloodstream in the early hours of application aresignificantly higher than that produced by an unheated DDDS 160, 165.The therapeutic serum fentanyl concentration varies from person toperson. For example some people respond to levels above 0.2 ng/mL.Referring to FIG. 6, this 0.2 ng/mL concentration is achieved in aboutone-third the amount of time for a heated system than for a non-heatedsystem (i.e., about 70 minutes as compared with about 210 minutes).

After a period of time when the exothermic reaction of temperaturecontrol apparatus 150 slowly stops generating heat, the fentanylconcentration in the bloodstream starts to gradually approach the normalsteady state fentanyl concentrations in the bloodstream which wouldultimately be seen with an unheated DDDS 160, 165, given a sufficientamount of time. As a result, the temperature control apparatus 150significantly shortens the onset time of Duragesic-50.RTM. withoutsignificantly altering its steady state delivery rates. Thus, theimportant advantage provided by this approach is that the onset time ofa DDDS 160, 165 already in clinical use can be shortened withoutsignificantly altering its steady state delivery rates which are notonly adequate, but also familiar to the caregivers and the patients.

EXAMPLE 8

A further example of using the embodiment of the present inventionillustrated in FIGS. 8-12 comprises using the temperature controlapparatus 150 for a sustained high absorption rate of an analgesicmaterial from the DDDS 160, 165. Cancer patient's tend to develop atolerance for fentanyl (and other analgesic materials) after extendeduse. For example, if a patient becomes tolerant to a Duragesic-100.RTM.(100 micrograms/hour deliver rate) dermal patch, a care giver may applyboth a Duragesic-100.RTM. and a Duragesic-50.RTM. (50 micrograms/hourdelivery rate) to treat the patient's cancer pain. However, instead ofusing two Duragesic.RTM. patches, a care giver can use aDuragesic-75.RTM. (75 micrograms/hour delivery rate) patch inconjunction with the temperature control apparatus 150, preferablydesigned to last between about 12 and 24 hours, to increase the fentanylabsorption. The care giver replaces the heating patch, after thedesigned heating during is over, with another heating patch to maintaina desired temperature, and continues to do so until the fentanyl in theDuragesic-75.RTM. patch can no longer supply a therapeutic amount offentanyl. It is, of course, understood that the temperature controlapparatus 150 may be designed to last as long as the expected usage timeof the Duragesic-75.RTM. dermal patch.

Heating patches with different heating temperatures may be used toachieve different increased levels of fentanyl deliver rates.

EXAMPLE 9

Yet still another example of using the embodiment of the presentinvention illustrated in FIGS. 8-12 again comprises using thetemperature control apparatus 150 for decreasing onset time of ananalgesic material from the DDDS 160, 165. By way of example, a localanaesthetic, such as a eutectic mixture of lidocaine and tetracaine, canbe administer with a DDDS 160, 165 to numb the skin 134 before a painfulmedical procedure. A faster onset and deeper numbing effect within ashort time can be achieved by placing the temperature control apparatus150 over the DDDS 160, 165, wherein the temperature control apparatus150 is capable of providing heating the skin to a narrow range betweenabout 37.degree. C. and 41.degree. C., preferably between 39.degree. C.and 40.degree. C., for at least 30 minutes. The skin 134 should be numbin 30 minute or less, which is much shorter than that without heating.Depending on the original skin temperature, it is believed that suchheating will reduce the onset time by about 60% of the onset timewithout heating.

EXAMPLE 10

Still another example of using the embodiment of the present inventionillustrated in FIGS. 8-12 again comprises using the temperature controlapparatus 150 for increasing the solubility of an analgesic from theDDDS 160, 165. By way of example, a formulation may be designed tocontain an analgesic which has such low solubility in the formulationthat a significant portion is in the form of undissolved paritcles, andthe solubility increases with increasing the temperature of theformulation.

A patient places such a DDDS 160, 165 on his skin. If the amount of theanalgesic compound the patient receives from the DDDS 160, 165 is notsufficient, the patient places the temperature control apparatus 150 onor over the DDDS 160, 165. The heat generated in the temperature controlapparatus 150 increases the temperature of the formulation in the DDDS160, 165 and maintains the increased temperature for a significant partor substantially the entire length of the DDDS 160, 165 application. Theincreased temperature in the formulation increases the solubility of theanalgesic compound in the formulation. Consequently, more analgesiccompounds are dissolved in the formulation which gives higher drivingforce for the transdermal permeation of the analgesic compound. As aresult, more of the analgesic compound enters the patient's body.

Another variation of this example is for the treatment of breakthroughpain. If the solubility of the analgesic compound in a formulation inthe DDDS 160, 165 is sufficient to treat baseline pain, but notbreakthrough pain, a patient can place the temperature control apparatus150 on or over the DDDS 160, 165 when an episode of breakthrough painoccurs. The increased solubility of the analgesic compound in theformulation results in the patient obtaining more analgesic compound totreat the breakthrough pain. The heating from the temperature controlapparatus can be discontinued after the patient determines that the painis under control.

Although Examples 1-10 discuss the application of specific drugs, it is,of course, understood that the present invention is not limited to anyparticular drug(s). It is understood that a considerable variety ofdrugs classes and specific drugs may be used with the present invention.The drug classes can include without limitation androgen, estrogen,non-steroidal anti-inflammatory agents, anti-hypertensive agents,analgesic agents, anti-depressants, antibiotics, anti-cancer agents,local anesthetics, antiemetics, anti-infectants, contraceptives,anti-diabetic agents, steroids, anti-allergy agents, anti-migraineagents, agents for smoking cessation, and anti-obesity agents. Specificdrugs can include without limitation nicotine, testosterone, estradiol,nitroglycerin, clonidine, dexamethasone, wintergreen oil, tetracaine,lidocaine, fentanyl, sufentanil, progestrone, insulin, Vitamin A,Vitamin C, Vitamin E, prilocaine, bupivacaine, sumatriptan, anddihydroergotamine.

EXAMPLE 11

Yet still another example of using the embodiment of the presentinvention illustrated in FIGS. 8-12 again comprises using thetemperature control apparatus 150 for maintaining a stable temperaturefor the DDDS 160, 165. Certain drugs have relatively low therapeuticindices, meaning that the differences between the therapeutic dose andthe dose which can cause serious and/or undesired side effects aresmall. Thus, dermal delivery of such drugs can be dangerous (over-dose)or ineffective (under-dose), especially for individuals whose skin areexposed to highly variable ambient temperatures, such as people workingoutdoors in extreme weather conditions. The variations in ambienttemperature can cause variations in skin temperature which cansignificantly change the ultimate dermal absorption of the drugs.Covering a DDDS 160, 165 containing a low therapeutic indices drug withthe temperature control apparatus 150 can regulate the skin temperatureto a narrower range and reduce the variation in dermal drug absorption.Drugs and classes of drugs that may benefit from this method include,but are not limited to, drugs such as nicotine, nitroglycerin,clonidine, fentanyl, sufentanil, and insulin; and classes of drugs suchas non-steroidal anti-inflammatory agents, anti-hypertensive agents,analgesic agents, anti-diabetic agents, and anti-migraine agents.

FIGS. 13-19 illustrates another embodiment of a temperature controlapparatus 170. FIG. 13 illustrates the temperature control apparatus 170which is similar to the embodiment of FIG. 8, but comprises atemperature regulating mechanism 108 which is made up of a plurality ofchambers 172 separated by non-air permeable walls 174. The temperatureregulating mechanism 108 is substantially surrounded by a bottom wall102, a top wall 104, and side walls 152. Again, the temperatureregulating mechanism 108 preferably comprises a composition of activatedcarbon, iron powder, sodium chloride, water, and, optionally, saw dust,which is disposed in each of the chambers 172. The top wall 104 ispreferably also a flexible non-air permeable material having a pluralityof holes 114 therethrough, preferably, a row of holes 114 for eachchamber 172. An air permeable membrane 116 is disposed between the topwall 104 and the temperature regulating mechanism 108 to regulate theamount of air reaching the temperature regulating mechanism 108 throughthe holes 114. The top wall 104 can have at least one cover covering theplurality of holes 114 for the regulation of the air into the chambers172. As illustrated in FIG. 13, three covers are layered on the top wall104. A first cover layer 176 is affixed to the top wall 104 and hasopenings 178 (see FIG. 17) to expose 2 out of 3 holes 114. A secondcover layer 182 is affixed to the first cover layer 176 and has opening184 (see FIG. 15) to expose 1 out of 3 holes 114. A top cover 186, whichhas no openings, is affixed to the second cover layer 182. Thus, apatient has a various opinions on what percentage of chambers 172 toexpose to ambient air. If the heat generated from one third of thechambers is required, the top cover 186 is removed, as shown in FIGS. 14and 15. If the heat generated from two thirds of the chambers isrequired or if another additional heat is needed after the depletion ofthe first one-third of the temperature regulating mechanism 108, the topcover 186 and the second cover layer are removed, as shown in FIGS. 16and 17. If the heat generated from all of the chambers is required or ifanother additional heat is needed after the depletion of the first andsecond one-third of the temperature regulating mechanism 108, the topcover 186, the second cover layer 182, and the first cover layer 176 areremoved, as shown in FIGS. 18 and 19. It is, of course, understood thatmore or less cover layers can be used with any number of holes toresults in any desired amounts of the temperature regulating mechanism108 being activated.

Thus, by way of example a patient can have a number of choices in usingthe temperature control apparatus 170, such for the suppression ofbreakthrough pain. When the breakthrough pain occurs, the patent placesthe temperature control apparatus 170 over an analgesic material DDDSand can do any of the following:

1) Activate a particular number or percent of chambers 172 by removingthe requisite covers depending on how much additional analgesic materialis required to treat the breakthrough pain. The covers can be preferablyreplaced to stop the exothermic reaction when no more additionalanalgesic material is required.

2) Activate a particular number or percent of chambers 172, exhaust theheat generating capacity of those chambers 172, and then activate other(non-activated) chambers 172. This extends the heating duration of thetemperature control apparatus 170. The duration of the total heatingtime is determined by the typical duration of the particular patient'sbreakthrough pain.

3) Activate enough chambers 172 to treat one episode of breakthroughpain, and leave the heating patch in place. When the next episode ofbreakthrough pain occurs, activate unused chambers 172.

FIG. 20 illustrates a dermal drug delivery system 190 (hereinafter “DDDS190”) having a rate limiting membrane 192. The structure of DDDS 190 issimilar to that of FIG. 3. However, the DDDS 190 includes a ratelimiting membrane 192 which resides between the drug formulation 128 andthe skin 134 of a patient.

Generally, the permeability of the drug in the drug formulation 128through the rate limiting member 192 is significantly lower than thepermeability of the drug in the drug formulation 128 into the skin of anaverage patient. Rate limiting membranes 192 are used to minimize thevariation in overall permeation, and to regulate the amount of drugdelivered to the patient so that overdosing does not occur. Anotheraspect of the present invention is the use of a temperature sensitiverate limiting membrane, such that the drug permeation rate through therate limiting membrane increases significantly with increasingtemperature. With such a DDDS 190, the above discussed temperaturecontrol mechanisms 100 (FIGS. 1 & 2), 150 (FIG. 8), and 170 (FIG. 13)can be used to increase the drug delivery rate across the rate limitingmembrane 192 to treat breakthrough pain, reduce onset time, increasesteady state delivery rate, or other advantages discussed above.

The possible temperature control mechanisms are not limited to theexothermic reaction mixture of iron powder, activated carbon, salt,water, and sawdust, as discussed above. FIG. 21 illustrates an electrictemperature control mechanism 200 comprising an electric heating element202 surrounded by a bottom wall 102, a top wall 104, and side walls 152(similar to FIG. 8). The side walls 152, preferably, extend a distancebelow the bottom wall 102 to define a cavity 154. It is, of course,understood that the electric heating element 202 does not have to havethe side walls 152 forming a cavity 154.

The bottom wall 102 and the side walls 152 are preferably made of aflexible non-air permeable material, such as non-air permeableclosed-cell foam material. A portion of the bottom of the temperaturecontrol apparatus 200 includes an adhesive material 112 on the bottom ofthe side walls 152 and, preferably, includes a second adhesive material156 in the bottom of the bottom wall 102, wherein the second adhesivematerial 156 is preferably less adhesive than the adhesive material 112.The electric heating element 202 preferably comprises a flexibleresistor plate that can generate heat when supplied with an electriccurrent through traces 206, 208. The electric current is preferablysupplied from a battery 212 attached to a control mechanism 214, and anelectronic switch 216. The battery 212, the control mechanism 214, andthe electronic switch 216 are preferably attached to the top surface ofthe top wall 104. The electric heating element 202 is activated bytriggering the electronic switch 216 which begins the flow of electriccurrent from the battery 212 to the electric heating element 202. Atemperature sensor 218, such as a thermistor, is preferably attached tothe bottom of the bottom wall 102 and sends a signal (corresponding tothe temperature at the bottom of the bottom wall 102) through electrictrace 222 to the control mechanism 214. The control mechanism 214regulates the flow of current to the electric heating element 202, sothat the electric heating element 202 quickly brines the temperature ata contact surface between the bottom wall 102 and a top of a DDDS (notshown) to a pre-determined level and maintains the temperature at thatpre-determined level. The following features may be incorporated intothe control mechanism 214: 1) a mechanism that allows a physician orcare giver set the length of each heating period for each patient, whichallows the physician to limit the heating, and hence the extra drug thatthe patient can get based on the conditions of the patient; 2) amechanism that allows the physician or care giver to set the minimumtime between the heating periods, and hence how often the patient canget the extra drug through increase heat; 3) a mechanism that allows thephysician or care giver to set a pre-determined temperature; and/or 4) amechanism that allows the physician or care giver to control the heatingtemperature profile, such as gradually increasing heating temperature ordecreasing temperature over a predetermined period of time. Thesefeatures can potentially give simple DDDSs a variety of control optionsfor the physician and/or the patient on the qunantity and timing of thedelivery of extra drug.

EXAMPLE 12

An example of using the embodiment of the present invention, such asillustrated in FIG. 21, includes using the temperature control mechanism200 for decreasing onset time of a local anesthetic comprisingapproximately 14% tetracaine/lidocaine eutectic mixture by weight; 8.6%polyvinyl alcohol (PVA) by weight, 0.17% sodium hydroxide (NaOH) byweight, and the remainder water (H.sub.2 O). The local anesthetic, inthe form of a thin patch, was placed on a volunteer's left forearm andthe temperature control mechanism 200, set to maintain a 41.degree. C.temperature, was placed over the local anesthetic. The local anestheticwas also placed on a volunteer's right forearm (at a different time) andleft at room temperature (about 24.degree. C.). The results arepresented in Table D, wherein the effect of the local anesthetic wasmeasure by a pain score when the skin is poked by a blunt object. Thepain score is defined as follows:

Score Effect 0 No effect 1 Between no numbness and medium numb 2 Mediumnumb 3 almost completely numb 4 completely numb, but not deep 5completely numb and deep

TABLE D Time (minutes) Pain Score with Heating Pain Score w/o Heating 154 2 20 5 3 25 4 30 5

Thus, it can be seen that heating reduced the onset time of complete anddeep numbness by approximately 33%.

EXAMPLE 13

Another example of using the embodiment of the present invention, suchas illustrated in FIG. 21, includes using the temperature controlmechanism 200 for a sustained high absorption rate of an analgesicmaterial from the DDDS 160, 165. Cancer patient's tend to develop atolerance for fentanyl (and other analgesic materials) after extendeduse. For example, if a cancer patient becomes tolerant to aDuragesic-100.RTM. (100 micrograms/hour deliver rate) dermal patch, acare giver may apply an electric heating device, such as temperaturecontrol mechanism 200, on a Duragesic-100.RTM. patch and sets thetemperature to heat the skin surface to 38.degree. C. to obtain a higherrate of fentanyl delivery from the Duragesic-100.RTM. patch for treatingthe patient's cancer pain. However, if, after a duration of treatment,the cancer patient becomes tolerant the fentanyl delivery rate at38.degree. C., the care giver can adjust the temperature controlmechanism 200 on the of Duragesic-100.RTM. patch to heat the skinsurface to 40.degree. C. to obtain an even higher rate of fentanyldelivery from the Duragesic-100.RTM. patch for treating the patient'scancer pain.

FIG. 22 illustrates another embodiment of a temperature controlapparatus 240 comprising a substantially flat, flexible bag 242 filledwith a supercooled liquid 244, such as a concentrated solution of sodiumacetate. A bottom portion of the bag 242, preferably, includes anadhesive material 246. The bag 242 is preferably slightly larger thanthe DDDS 160 such that the adhesive material 246 may contact and adhereto the skin 134. The bag 242 further includes a triggering mechanism248, such as a metal strip. For example, when a patient wearing a DDDScontaining an appropriate analgesic material feels the imminent onset ofbreakthrough pain, the bag 242 is placed over the DDDS 160. Thetriggering mechanism 248 is activated (such as by bending a metal strip)which triggers crystallization in the supercooled liquid. The heatgenerated by the crystallization (phase transition) increases the speedof transport of analgesic material into the body and the speeds therelease of analgesic material from the depot sites in the skin and thesub-skin tissues. As a result the patient gets a rapid delivery of extraanalgesic material to treat breakthrough pain. Usually, the heatgenerated by a phase transition can not be sustained over extended time,but may be enough to release adequate amount of analgesic material fromthe depot sites in the tissues under the skin to treat the breakthroughpain. The advantage of the temperature control apparatus 240 is that itis reusable. After use, the temperature control apparatus 240 can beplaced in hot water and then cooled to room temperature to transfer thesolidified contents in the bag back to a supercooled liquid 244.

EXAMPLE 14

An example of using the embodiment of the present invention illustratedin FIGS. 23-24 comprises using a temperature control apparatus 300 whichis capable of heating and cooling, such that the rate of absorption of adrug formulation in a DDDS can be increased or decreased, as needed.

For example, as shown in FIG. 23, if the level of the drug in thepatient's system requires adjusting, the temperature control apparatus300 is placed on a DDDS 160. Heating will result in an increase in drugabsorption (as previously discussed) and cooling will reduce drugabsorption to prevent overdose. FIG. 23 illustrates the temperaturecontrol apparatus 300 as a thermoelectric module which is be used forboth heating or cooling. The temperature control apparatus 300 functionsas a small heat pump, wherein a low voltage DC power source 304 providesa current in one direction 306 to a thermoelectric unit 310 whichresults in heating on a first side 308 (preferably a ceramic substrace)of the temperature control apparatus 300 and cooling on a second side312 (preferably a finned dissipation structure) of the temperaturecontrol apparatus 300. If the current direction is reversed, the firstside 308 will cool and the second side will heat.

The temperature control apparatus 300 may be control with a closed looptemperature controller 314, as shown in FIG. 24. The temperaturecontroller 314 comprises a positive DC node 316 and a negative DC node318 supplying circuit to a primary circuit 320. The primary circuit 320delivers an electrical signal 322 through a voltage amplifier 324 and apower amplifier 326 to the thermoelectric unit 310. The primary circuit320 further includes a temperature sensor 328 receiving a temperaturesignal 330 from the thermoelectric unit 310, and further includes atemperature adjustment mechanism 332, which adjusts the electricalsignal 322.

A variety of drugs and drug classes can be utilized with suchtreatments. The drugs include, but are not limited to, nicotine,nitroglycerin, clonidine, dexamethasone, fentanyl, sufentanil, andinsulin. The drug classes include, but are not limited to, androgen,non-steroidal anti-inflammatory agents, anti-hypertensive agents,analgesic agents, anti-depressants, anti-cancer agents, anti-diabeticagents, steroids, anti-migraine agents, anti-asthma agents, and agentsfor smoking cessation.

It is, of course, understood that the heating devices discussed abovecould be replaced by an infrared heating device with a feedbackmechanism. All of the controls and variations in controls discussedabove would apply to such an infrared heating device. The advantage ofinfrared radiation over simple heat is that the former, with properwavelengths, penetrates deeper into a patient's skin.

Another aspect of the present invention is to use heat and otherphysical means, such as ultrasound, microwave, electric current, andvibration, to improve absorption of drugs from depot/storage sites. Suchdepot/storage sites may exist as a result of a drug administered from adermal patch or a drug directly injected or implanted under the skinsurface.

The kind of formulations that may respond to the physical inducing meansdiscussed above are:

Ultrasound: particles containing drug formulation that can break down insize when treated with ultrasound.

Microwave: drugs that have limited solubility in surrounding body fluid,but the solubility increases significantly with increasing temperature;and solid formulations whose erosion/degradation speed can besignificantly increased by increasing flow/exchange of body fluidsurrounding it.

Electricity: drugs that exist in ionized form in the formulations and/orsurrounding body fluid.

Vibration: drugs that have limited solubility in body fluid; solidformulations whose erosion/degradation speed can be significantlyincreased by increasing flow/exchange of body fluid surrounding it.

EXAMPLE 15

One example of enhanced depot site absorption using the embodiment ofthe present invention illustrated in FIGS. 1 and 2 for administeringanalgesic material for pain relief consists of a patient or care giverplacing the DDDS, such as a fentanyl-containing DDDS, on the skin of thepatient at a first location. After sufficient depletion of the drug inthe DDDS, the DDDS is removed and a second DDDS is placed on the skin ofthe patient at a second location to continue drug delivery. If anepisode of breakthrough pain occurs, the temperature control apparatus100 can be applied directly to the patient's skin 134 at the firstlocation (the DDDS is no longer present), as shown in FIG. 25. The heatfrom the temperature control device 100 increases the speed of drugrelease from the depot site 252 in the first skin site and the tissuesthereunder to give an increased drug absorption into the systemiccirculation 254 to treat the breakthrough pain.

EXAMPLE 16

An example of storage site absorption using the embodiment of thepresent invention illustrated in FIGS. 1 and 2 consists of a patient orcare giver introducing an extended release insulin into his skin byinjection or other method such as ultrasound speed hitting (such asproducts similar to those developed by Powderject Pharmaceutical, UnitedKingdom). In the extended release insulin formulation, most of theinsulin molecules are in crystalline form. After injection, insulin isreleased from the crystalline from slowly as the crystals slowlydissolve in the surrounding body fluid. This provides a baseline insulinrelease into the systemic circulation. However, the patient needsadditional insulin above the baseline release to suppress sugar frommeals. Thus, before each meal the patient places a temperature controlapparatus 100, preferably designed to control heat for a predeterminedtime (i.e., between about 15 and 60 minutes), onto the skin over theinjection site where the injected extended release insulin formulationresides. The heat from the temperature control apparatus 100 increasesflow of the blood and another body fluid in the tissues surrounding theextended insulin formulation, which increases the dissolution speed ofthe insulin and carries the insulin into the systemic circulation athigher rate. The heating duration of the temperature control device is,preferably, designed to last just long enough to release the adequateamount of extra insulin to deal with the sugar from the meal. Thus, thepatient receives proper insulin absorption adjustment from the extendedrelease formulation, and does not have to make a choice between takingadditional insulin shots before meals or suffer the physiologicalconsequences caused by high blood sugar from the meals.

EXAMPLE 17

Another example of storage site absorption using the embodiment of thepresent invention illustrated in FIGS. 1 and 2 consists of a patient orcare giver injecting a drug mixed in controlled release particles underthe skin surface. By way of example, a controlled release formulation ofanalgesics may comprise an analgesic, such as sufentanil, alfentanil,remifentanil, and morphine, which is incorporated into a controlledrelease drug delivery system (such as Atrigel.TM. by Atrix Laboratories,Inc., Fort Collins, Colo., U.S.A) comprising a biodegradable,biocompatible polymer(s) [i.e., poly(DL-lactide),poly(DL-lactide-co-glycolide),poly(DL-lactide-co-.epsilon.-caprolactone), polycaprolactone, or acombination thereof] in a biodegradable solvent (i.e.,N-methyl-2-pyrrolidone). The controlled release formulation is generallyinjected into a patient within 3 cm, preferably within 1 cm, and mostpreferably 0.3 cm, from the skin to control his cancer pain.

It is understood that any homopolymer or copolymer of lactic andglycolic acid can be utilized. The lactic/glycolic acid polymers aresolids, wherein the drug and polymers are both dissolved in abiodegradable solvent. After the injection, the biodegradable solventdiffuses out leaving behind the polymer(s) in the form of precipitated,biodegradable particles, which holds most of the sufentanil. As thepolymer particles gradually erodes/degrades, the sufentanil is releasedinto the systemic circulation to treat the cancer pain. The release rateof sufentanil is determined by how quickly the polymer particleserodes/degrades in the body.

The active drug may also be incorporated and delivered into the storagesite using different methods, such as mixing the drug with thebiodegradable, biocompatible polymer(s) in a solvent, evaporating thesolvent to obtain polymer particles mixed with the active drug. The sizeof the drug containing polymer particles should be, small enough to beincorporated (not dissolved) into a suspension in a liquid (preferablyan aqueous liquid). The suspension is injected into the patient's tissueproximate the skin surface. The liquid quickly leaves the depot site,leaving behind a polymer implant containing the active drug. The releaseof active drug from the polymer implant can be increased in the mannerdescribed above.

Regardless of the implantation method, the normal release rate ofsufentanil is usually sufficient to treat the patients baseline cancerpain, but not enough to treat breakthrough pain. When the patient feelsa breakthrough pain is coming, he places a temperature control apparatus100 over the skin site under which the formulation was injected. Theincreased blood/body fluid flow caused by the heat increases theerosion/degradation speed of the polymer particles and hence the speedof release of sufentanil. When the breakthrough pain is over, thepatient stops the heating (such as by removing the heating patch orcovering the holes 114 on the top wall 104—see FIG. 2) and the polymerparticle erosion/degradation speed gradually returns to normal whichreturns the sufentanil release rate back to a normal, pre-heated rate.

EXAMPLE 18

The effects of heating on the release of a drug incorporated in abiocompatible, biodegradable polymer matrix were examined. An anesthetic(i.e., lidocaine) was incorporated into the polymer matrix (i.e.,lactide/glycolide polymer) to form an anesthetic drug/polymercomposition. The anesthetic drug/polymer composition may be used forinjecting/planting under the skin of a patient, wherein the drug isgradually released into the body as the polymer matrix slowly erodes inthe body.

The anesthetic drug/polymer composition was made by dissolving one tenthof one gram of lactide/glycolide polymer (Medisorb Grade 8515DL,Medisorb Technologies International, L.P., Cincinnati, Ohio, U.S.A) and0.1 gram of lidocaine base in 2 grams of acetone to form a solution.Approximately 5 mL of water (pH adjusted to above 8) was slowly addedinto the solution while the solution was stirred by a rapidly rotatingTeflon coated magnetic bar. A Medisorb-lidocaine mixture precipitatedout as a textured material attached on the magnetic bar and as fineparticles suspended in the solution. Approximately 0.5 mL of thesolution containing the fine particles were injected into a 0.2micrometer PTFE filter (Nalgene, 25 mm). Normal saline was infusedthrough the filter via a 3M.TM. 3000 Modular Infusion Pump at a rate of2 ml/hr for approximately 7 days. This was to wash away the lidocainethat was not incorporated in to the Medisorb matrix and particlessmaller than 0.2 micrometer, while lidocaine-polymer particles biggerthan 0.2 micrometer were trapped in the filter. The particles slowlydegraded due to hydrolysis and thus gradually releases licocaine to thesaline passing through the filter.

A blunt needle was tightly attached to the exit end of the filter, and athin plastic tube was attached to the blunt needle. Filtered solutionfrom the distal end of the thin plastic tube was collected according thefollowing steps:

Step 1: Filter at room temperature (about 24.degree. C.) and collect thefiltered solution into a glass vial for approximately 1 hour.

Step 2: Immerse the filter into a 36.degree. C. (approximate) waterbath, wait approximately 1 hour, and collect the filtered solution fromthe thin tube for approximately 1 hour.

Step 3: Increase the temperature of the water bath to about 44.degree.C., wait approximately 1 hour, and collect the filtered solution forapproximately 1 hour.

Step 4: Take the filter out of the water bath and leave at roomtemperature (about 24.degree. C.) for approximately 0.5 hours, collectthe filter solution for approximately 1 hour.

Step 5: Repeat Step 4 after approximately 2 hours.

Saline was infused through the filter at the 2 mL/hour rate for theentire experiment. The solution coming out of the thin plastic tubduring non-collecting time were discarded. Concentrations of lidocainein above collected solutions were determined by an HPLC (HighPerformance Liquid Chromatography) method.

Lidocaine release rates from the polymer matrix at differenttemperatures were calculated from lidocaine concentrations in thecollected samples. The release rates are shown in Table E, as follows:

TABLE E Lidocaine Release Rate Step Temperature (mcg/hour) 1 24.degree.C. 0.36 2 36.degree. C. 0.61 3 44.degree. C. 1.59 4 24.degree. C. 0.47 524.degree. C. 0.38

As the results demonstrate, the lidocaine release rate increased whentemperature at the filter (and hence the temperature of thelidocaine-polymer particles) was increased, and decreased when thetemperature was decreased. Although the filter temperature in Steps 4and 5 were the same, the lidocaine release rate in Step 5 was lower thanthat in Step 4, land approaches that in Step 1.

Although the total quantities of Medisorb and lidocaine in the filterwere not measured, the relative differences in the lidocaine releaserates at different temperatures demonstrate that lidocaine release ratefrom Medisorb polymer increases with temperature. The finding thatlidocaine release rate in Step 5 was lower than that in Step 4 suggestthat the release rate decreases gradually after the temperature islowered.

Since the degradation (hydrolysis) of Medisorb polymer is believed tocontrol the release rates, these results suggest that Medisorb polymerdegradation rate increases with increasing temperature. This suggeststhat the release rate of any drug incorporated in the Medisorb matrix(or other similar materials) and injected into the body can be increasedby increasing temperature. In addition to increasing hydrolysis rate ofthe Medisorb-lidocaine particles, heat is also expected to increase theflow of body fluid surrounding the particles in the storage site inactual application, which should cause an additional increase in thedrug absorption rate.

Another experiment was conducted on the Medisorb (same type as discussedabove). A first sample of the Medisorb (transparent beads) weighing0.1024 grams was placed in a first glass vial with 9.9024 grams of 0.9%sodium chloride injection solution. The first glass vial was sealed withparafilm and placed in an oven which maintained a temperature of about43.degree. C. A second sample of the Medisorb weighing 0.1028 grams wasplaced in a second glass vial with 9.9167 grams of 0.9% sodium chlorideinjection solution. The second glass vial was sealed with parafilm andplaced in a room with a temperature of about 23.degree. C.

After 29 days, few visible change had occurred to the Medisorb held atroom temperature (second sample). However, the Medisorb held at about43.degree. C. changed from a transparent material to a milky-white colorwith smoothed edges. The Medisorb beads also appeared smaller than theoriginal size. This simple experiment demonstrates that the degradationrate of the Medisorb polymer increases with increasing temperature.

EXAMPLE 19

Still another example of storage site absorption using the embodiment ofthe present invention illustrated in FIGS. 1 and 2 consists of a patientor care giver implanting a solid piece (i.e., plate, rod, or the like)made of a biocompatible, bioerodable material(s), such as listed inExample 16, under the skin surface. By way of example, insulin can beincorporated into such a material. The insulin-containing solid piece isimplanted into a diabetic patient in a position within 3 cm, preferablywithin 1 cm, and most preferably within 0.3 cm, from the skin. Theinsulin release rate from the solid piece is designed to be sufficientto provide the baseline insulin need for extended period of time (e.g.,a few months). Before each meal, the patient places the temperaturecontrol apparatus 100, preferably with a pre-determined heatingduration, on to the skin site under which the solid piece resides. Theheat from the temperature control apparatus 100 increases the flow ofblood or other body fluid surrounding the solid piece, thus increasesthe erosion/degradation of the solid piece and delivers extra insulin tothe systemic circulation to suppress the sugar from the meals. After thepredetermined duration of temperature control apparatus 100 is over orafter the patient discontinues the heating from the temperature controlapparatus 100, the erosion/degradation rate of the solid piece graduallyreturns to normal, as does the insulin release rate.

Furthermore, such a system can be used with testosterone in a solidpiece which implanted in the patient's skin. Preferably, the temperaturecontrol apparatus 100 is designed to last substantially longer (i.e.,approximately 6-10 hours). The patent applies the temperature controlapparatus 100 on the skin site under which the solid piece resides toobtain increased testosterone levels in the blood in the period frommorning to evening when testosterone is most needed.

Although only a small number of drugs have been disclosed in Examples13-18, any drug used in a treatment that fits the following descriptionmay potentially benefit from the methods: 1) the treatment requires thatthe drug have a baseline deliver rate over long treatment duration (suchas longer than a day, preferably over a week), and 2) the treatmentrequires the drug to have increased delivery rates for a period orperiods of time during the long treatment duration. A variety of drugsand drug classes can be utilized with such treatments. The drugsinclude, but are not limited to, nicotine, testosterone, estradiol,nitroglycerin, clonidine, dexamethasone, tetracaine, lidocaine,fentanyl, sufentanil, progestrone, insulin, prilocaine, bupivacaine,sumatriptan, and dihydroergotamine. The drug classes include, but arenot limited to, androgen, estrogen, non-steroidal anti-inflammatoryagents, anti-hypertensive agents, analgesic agents, anti-deperessants,antibiotics, anti-cancer agents, local anesthetics, antiemetics,anti-infectants, contraceptives, anti-diabetic agents, steroids,anti-allergy agents, anti-migraine agents, agents for smoking cessation,anti-asthma agents, and anti-obesity agents.

EXAMPLE 20

Still yet another example of storage site absorption using theembodiment of the present invention illustrated in FIGS. 1 and 2consists of a patient or care giver imbedding a drug into the depotsite. By way of example, a care giver can embed an anti-migraine drug,such as a powder form of dihydroergotamine, sumatriptan, or ergotamine,by hitting the drug into a depot site under the skin at high speed (suchas by a device manufactured by Powderject Pharmaceutical, UnitedKingdom) when a patient feels an episode of migraine headache isimminent. With the Powderjet device, the drug powder is accelerated to aspeed higher than the speed of sound and hit into the skin. Atemperature control apparatus 100, preferably lasting approximately 1hour, is immediately applied on the skin over the location of theembedded drug. The heat from the temperature control apparatus 100increases the speed of the body fluid flow surrounding the anti-migrainedrug and carries the anti-migraine drug into the systemic circulationfaster. As a result, therapeutical blood concentrations of theanti-migraine drug is reached earlier and in time to treat the migraineheadache.

This technique may also be used to deliver a preventative baselinerelease rate of a drug, such as anti-migraine drug or nitroglycerine. Aheating patch is then applied to release extra drug when a medicalepisode begins.

It is, of course, understood that the heating devices discussed abovecould be replaced by an infrared heating device or a microwave heatingdevice with a feedback mechanism. All the controls and variations incontrols discussed above would apply to such devices.

EXAMPLE 21

Ultrasound can be used to increase release rate of injected controlledrelease drug formulations, particularly, when the controlled releaseformulations are in the form of relatively large particles (i.e., 25 mmor larger). The controlled release formulation is injected into thepatient's tissues within 3 cm, preferably within 1 cm, and mostpreferably 0.3 cm from the skin. The erosion/degradation rate of theparticles determines the rate of release of the drug, and the steadystate release rate of the drug is designed to deliver a therapeuticallevel of drug to the patient. For analgesic drugs, the steady staterelease rate is usually slightly below that needed to treat an averageperson's post-operative pain. For a particular patient in whom thesteady state release rate is not sufficient (because of hispharmacokinetics and/or level of pain), an ultrasound is directed intoformulation and breaks the particles into smaller ones (this requiresthat the particles are capable of being broken by ultrasound).

This increases the surface area of the formulation exposed to thesurrounding body fluid, and hence increases the release rate for therest of the administration. This method allows the administration of alow release rate formulation which is safe, and then increasing therelease rate for patients who need higher delivery rates. The intensity,frequencies, and duration of ultrasound can be chosen to increase therelease rate to proper levels. Exemplary ultrasound treatment anddevices can be found in U.S. Pat. No. 4,948,587 issued Aug. 14, 1998 toKost et al., hereby incorporate herein by reference.

EXAMPLE 22

The generation of an electric potential on a portion of a patient's bodycan be used to increase release rate of injected controlled release drugformulations, particularly, when the controlled release formulationsexist in ionized form in the formulations and/or surrounding body fluid.For example, when a controlled release insulin is injected into adiabetic patient's skin, the normal release rate of insulin from thisformulation is controlled by the dissolution rate of the particles inwhich insulin resides wherein the normal release rate provides anadequate baseline insulin level in the patient. As shown in FIG. 26, thepatient places a first electrode 262 on the skin 134 over the injectionsite of the controlled release insulin formulation 264. A secondelectrode 266 is placed on a skin 134 in a position near the injectionsite of the controlled release insulin formulation 264 (i.e., at least afew centimeters away). Before each meal when the patient needs toincrease his blood insulin level to suppress sugar from the meal, thepatient connects the first electrode 262 and the second electrode 266with wires 268 and 270, respectively, to an electric current generatingdevice 272. The electric current generating device 272 introduces anelectrical potential between the first electrode 262 and the secondelectrode 266. Preferably, with the use of insulin, the electricalamperage should be in the range of between about 0.2 and 4 mA. Becauseat the physiological pH, insulin molecules carry net negative electriccharges, the first electrode 262 should have a negative charge whichpushes the negatively charged insulin away from the body fluidsurrounding the formulation and into the systemic circulation 254. Thismakes the insulin release faster. Preferably, the intensity and durationof the current can be altered with the electric current generatingdevice 272 to deliver the requisite therapeutic amount of extra insulin.

EXAMPLE 23

The generation of a vibration over the injection site of controlledrelease drug formulations can be used to increase release rate of theformulations, particularly, when the controlled release formulationshave limited solubility in body fluid or with solid formulations whoseerosion/degradation speed can be significantly increased by increasingflow/exchange of body fluid surrounding the solid formulation. Forexample, when a controlled release insulin is injected into a diabeticpatient's skin, the normal release rate of insulin from this formulationis controlled by the erosion/degradation or dissolution rate of theparticles in which insulin resides wherein the normal release rateprovides an adequate baseline insulin level in the patient. As shown inFIG. 27, before each meal, the patient places a vibration generatingdevice 282 on the skin 134 over the injection site of the controlledrelease insulin formulation 264. The vibration generating device 282,preferably, delivers vibration of between about 20 and 400 Hz. Thevibration agitates the body fluid (not shown) surrounding the controlledrelease insulin 264 and increases its circulation. As a result, moreinsulin is released from the controlled release insulin formulation 264to the systemic circulation 254 shortly before the meal to suppress thesugar from the meal. Preferably, the intensity and duration of thevibration can be altered with the vibration generating device 282 todeliver the requisite therapeutic amount of extra insulin.

Although only a few drugs have been disclosed in Examples 19-22, anydrug used in a treatment that fits the following description maypotentially benefit from the physical methods for inducing increasedrelease: 1) the treatment requires that the drug have a baseline deliverrate over long treatment duration (such as longer than a day, preferablyover a week), 2) the treatment requires the drug to have increaseddelivery rates for a period or periods of time during the long treatmentduration, and 3) the formulations respond to the one or more of thephysical methods for inducing increased release. A variety of drugs anddrug classes can be utilized with such treatments. The drugs include,but are not limited to, nicotine, testosterone, estradiol,nitroglycerin, clonidine, dexamethasone, tetracaine, lidocaine,fentanyl, sufentanil, progestrone, insulin, prilocaine, bupivacaine,sumatriptan, and dihydroergotamine. The drug classes include, but arenot limited to, androgen, estrogen, non-steroidal anti-inflammatoryagents, anti-hypertensive agents, analgesic agents, anti-depressants,antibiotics, anti-cancer agents, local anesthetics, antiemetics,anti-infectants, contraceptives, anti-diabetic agents, steroids,anti-allergy agents, anti-migraine agents, and agents for smokingcessation.

EXAMPLE 24

Another example of the present invention comprises using a temperaturecontrol apparatus 300, similar to that shown in FIG. 23, which iscapable of heating and cooling, such that the rate of absorption ofinjected controlled release drug formulation can be increased ordecreased, as needed.

For example, when a controlled release drug formulation is injected intoa patient's skin, the normal release rate of the drug from thisformulation is controlled by the erosion/degradation rate of theparticles in which the drug resides wherein the normal release rateprovides an adequate baseline drug level in the patient. As shown inFIG. 28, if the level of the drug in the patient's system requiresadjusting, the temperature control apparatus 300 is placed on the skin134 over the injection site of the controlled release drug formulation302. Heating will result in an increase in drug absorption (aspreviously discussed) and cooling will reduce drug absorption to preventoverdose. FIG. 23 illustrates the temperature control apparatus 300 as athermoelectric module which is be used for both heating or cooling. Thetemperature control apparatus 300 functions as a small heat pump,wherein a low voltage DC power source 304 provides a current in onedirection 306 to a thermoelectric unit 310 which results in heating on afirst side 308 (preferably a ceramic substrace) of the temperaturecontrol apparatus 300 and cooling on a second side 312 (preferably afinned dissipation structure) of the temperature control apparatus 300.If the current direction is reversed, the first side 308 will cool andthe second side will heat. The temperature control apparatus 300 may becontrol with a closed loop temperature controller, as shown previouslyin FIG. 24.

A variety of drugs and drug classes can be utilized with suchtreatments. The drugs include, but are not limited to, nicotine,nitroglycerin, clonidine, dexamethasone, fentanyl, sufentanil, andinsulin. The drug classes include, but are not limited to, androgen,non-steroidal anti-inflammatory agents, anti-hypertensive agents,analgesic agents, anti-depressants, anti-cancer agents, anti-diabeticagents, steroids, anti-migraine agents, and agents for smokingcessation.

EXAMPLE 25

Another example of the present invention comprises using the temperaturecontrol apparatus 300, as shown in FIG. 23, or any device which iscapable of cooling the skin in conjunction with an injectable liquiddrug delivery formulation containing thermal gel.

The main difference between a thermal gel and a regular gel is that athermal gel is a liquid in room temperature (i.e., about 20-25.degree.C.) and is a gel at body temperature (i.e., about 37.degree. C.),whereas, with regular gel, the viscosity of the gel generally lowerswith increasing temperature. Thus, while the thermal gel is at roomtemperature (i.e., in liquid form), a drug formulation is mixed into thethermal gel. The thermal gel/drug mixture may then be easily drawn intoa syringe and injected to the patient. Once in the patient's body, thethermal gel/drug mixture quickly solidifies into a gel. The gel thendissolves over time releasing the drug formulation into the patientsystemic circulation.

Using a cooling device, such as the temperature control apparatus shownin FIG. 23, the thermal gel/drug mixture which has solidified under theskin can be cooled to revert the gel back into a liquid. In a liquidstate, the drug formulation diffusion rate and release rate increase,thereby increasing the drug formulation present in the patient'ssystemic circulation when needed.

An example of a thermal gel is Smart Hydrogel.TM. developed by GelScience/GelMed and consists of an entangled network of two randomlygrafted polymers. One polymer is poly(acrylic acid) which is bioadhesiveand pH-responsive. The other polymer is a triblock copolymer containingpoly(propylene oxide) (“PPO”) and poly(ethylene oxide) (“PEO”) segmentsin the sequence PEO-PPO-PEO.

An example of using the present invention with a thermal gel is thedelivery of additional insulin to a diabetic patient prior to the intakeof food. The thermal gel containing the insulin can be injectedsubcutaneously in order to form a gel to release a continuous baselinedosage of insulin. At a meal when insulin is needed to absorb extrasugar in the circulation, the patient can apply the cooling device onthe skin adjacent the injection site and cool the injection site to atemperature below the gelling temperature of the thermal gel/insulinmixture. The gel will, of course, become a liquid and increase theinsulin level in the patient's body to compensated for the ingestedmeal. This process can be repeated many times until the injected thermalgel/insulin mixture is gone. The advantage of this drug delivery systemis that the diabetic patient can control insulin delivery during thecourse of a few days, even a few weeks, with only one injection.

EXAMPLE 26

As shown in FIG. 29, an insulating material can be incorporated with thecontrolled temperature apparatus to assist in not only minimizing thetemperature variation, but also increasing the temperature of the DDDSand the skin under it (by decreasing heat loss), each of which tend toincrease dermal drug absorption.

FIG. 29 illustrates a configuration similar to that illustrated in FIG.4 wherein the temperature control apparatus 100 of FIG. 2 is attached tothe DDDS 120 of FIG. 3. The DDDS 120 attached to a portion of the skin134 of a patient. An insulating sleeve 350 abuts the skin 134 andencases a substantial portion of the temperature control apparatus 100and the DDDS 120.

FIG. 30 illustrates another insulating sleeve 360 made of an insulatingmaterial, such as closed-cell foam tape, with adhesive edges 362attached to a patient's skin 134, slightly larger than and covering aDDDS 364. FIG. 31 illustrates the insulating sleeve 360 covering aheating apparatus 366 and the DDDS 364 attached to a patient's skin 134.FIG. 32 illustrates the insulating sleeve 360 covering an area over theskin 134 where an injected/implanted/controlled/extended release drugformulation 368 has been located.

EXAMPLE 27

Another application of the present invention involves the use of aheating device, such as discussed above, in conjunction with a typicalliquid drug injection. For some drugs, increased speed of absorptioninto the systemic circulation after they are injected into the body mayprovide treatment to the patients. For instance, to be effective, theanti-migraine drug, dihydroergotamine, must reach an effectiveconcentration level in the blood stream within a certain amount of timefrom the onset of the migraine attack or the drug will be ineffective.Currently, a drug's absorption into the patient's systemic circulationcannot be altered after it is injected. Thus, the controlled heatingaspect of the present invention can be used to increase the absorptionspeed of subcutaneously and intramuscularly injected drugs.

For example, after a drug is injected subcutaneously or intramuscularly,a heating patch, such as described in the above examples, may be placedon the skin under which the injected drug resides. The heating increasesthe circulation of body fluid surrounding the injected drug, increasesthe permeability of blood vessel walls in the surrounding tissue, and,thus, results in increased speed of absorption of the drug into thesystemic circulation.

Such a method would be useful for drugs which are injected into a partof the body that can be heated by a heating means on or outside the skinand whose effect can be improved by increased absorption speed into thesystemic circulation or deeper tissues. Such drugs may include;anti-migraine agents, anti-hypertensive agents, analgesics, antiemetics,cardiovascular agents. Specific drugs may include dihydroergotamine,ergotamine, sumatriptan, rizatriptan, zolmitriptan, and other selective5-hydroxytryptamine receptor subtype agonists, morphine and othernarcotic agents, atropine, nitroglycerin, fentanyl, sufentanil,alfentanil, and meperidine.

Since increased absorption speed into the systemic circulation usuallycan cause higher peak concentrations in the blood, this technology mayalso be used to increase peak blood concentrations of drugs that areinjected subcutaneously and intramuscularly.

Some drugs need to be injected intravenously because systemic absorptionfor subcutaneous and intramuscular injections take too long to takeeffect. However, intravenous injection is more difficult to perform andinvolves more risks. With the use of the present invention, theabsorption speed of some drugs may be increased enough so thatsubcutaneous or intramuscular injection can provide sufficient speed ofabsorption. Therefore, this technology may also be used for replacingintravenous injections with subcutaneous or intramuscular injections forsome drugs.

As a specific example, a patient may inject himself with sumatriptan ordihydroergotamine subcutaneously after he feels a migraine attack. Hethen removes a heating patch containing a heat generating mediumcomprising iron powder, activated carbon, water, sodium chloride, andsawdust (similar to Example 1) out of its air-tight container and placesit over the injection site. The heating patch quickly increases thetemperature of the skin under the heating patch into a narrow range of39-43.degree. C. and maintains it there for at least 15 minutes. Thecirculation speed of the body fluid surrounding the injected drug andthe permeability of the blood vessels in the surrounding tissues areboth increased by the heating. As a result, the drug enters the systemiccirculation and reaches the acting site more rapidly, and the patientreceives more rapid and/or better control of the migraine attack.

In another example, a nurse can inject morphine into a patient's muscletissue to treat severe pain. The nurse then places a heating patch, asdescribe above, over the injection site. The speed of morphineabsorption into the systemic circulation is increased as previouslydiscussed. As a result, the patient receives more rapid and/or betterpan control.

EXAMPLE 28

Another application of the present invention involves the use of aheating device, such as discussed above, to mimic circadian patterns.For example, testosterone or its derivatives, such as testosteroneenanthate and testosterone cypionate, can be injected intramuscularlyinto men to substitute or replace diminished or absent naturaltesticular hormone. Testosterone enanthate and testosterone cypionateare preferred over testosterone, as they have longer duration of actionthan testosterone. However, it is understood that testosterone or itsderivative, such a testosterone ester, may be incorporated into acontrolled release polymer matrix, such as homopolymer or copolymer oflactic and glycolic acid, preferably poly(DL-lactide),poly(DL-lactide-co-glycolide), and poly(DL-lactide-co-(-caprolactone)),to increase the duration of action. Following intramuscular injection,testosterone enanthate is absorbed gradually from the lipid tissue phaseat the injection site to provide a duration of action of up to 2-4weeks. However, natural blood testosterone concentrations in healthy manare higher in a day and lower in the night. So blood testosteroneconcentrations obtained from injected testosterone derivatives do notmimicking the natural circadian pattern.

By way of example, a patient can inject testosterone enanthate eithersubcutaneously or intramuscularly (if intramuscularly, the injectionshould be relatively close to the skin surface). The patient then placesa heating patch on the injection site every morning (until all theinjected testosterone enanthate is depleted). The heating patch quicklyincreases the temperature of the injection site to a narrow range, andmaintains it therefore a desirable duration of time (i.e., about 8hours). They heating causes increased release of testosterone enanthateand/or increased rate of conversion from testosterone enanthate totestosterone, and, thus, higher blood testosterone concentrations. The“used-up” patch is removed before a new heating patch is placed on thesame. Using this intermittent heat application technique, bloodtestosterone concentrations are low in the night and high in the day,thus mimicking the natural circadian pattern.

The present invention may be embodied in other specific forms withoutdeparting from its spirit of essential characteristics. The describedembodiments are to be considered in all respects only al illustrativeand not restrictive. The scope of the invention is, therefore, indicatedby the appended claims, rather than by the foregoing description. Allchanges which come within the meaning and range of equivalency of theclaims are to be embraced within their scope.

What is claimed and desired to be secured by Letters Patent is:
 1. Amethod of reducing an onset time of the effect of a drug in a targetarea of a human body comprising: administering a drug to a portion ifsaid human body; applying a temperature of modification apparatusproximate said drug being administered, said temperature modificationapparatus capable of generating controlled heat by exposing an oxygenactivated exothermic medium within the apparatus to a safe,pre-determined amount of oxygen; and heating the temperature of skinproximate said portion of said human body for a safe, pre-determinedamount of time and within a safe, pre-determined temperature range, saidtemperature modification apparatus to achieve said reduced onset time ofsaid drug in said targeted area.
 2. A method of reducing the onset timeof a drug in a targeted area of a human body comprising: administering adrug to a portion of said human body, wherein said administering saiddrug is a method selected from the group consisting of transdermalapplication, application of a dermal drug delivery system, subcutaneousadministration, and intramuscular administration; applying an apparatuscapable of generating heat proximate said drug being administered, saidapparatus capable of generating controlled heat proximate said portionof said human body by exposing an oxygen activated exothermic mediumwithin the apparatus to a safe, pre-determined amount of oxygen, thusheating the skin proximate said portion of said human body to a safe,pre-determined temperature and for a safe, pre-determined amount of timeto achieve said reduced onset time of said drug.
 3. A method of reducingthe onset time of an analgesic in a targeted area of a human bodycomprising: administering said analgesic into a site of said human bodywithin about 3 centimeters from the surface of the skin proximate saidsite; applying a temperature modification apparatus proximate said skinproximate said site, said temperature modification apparatus capable ofgenerating controlled heat proximate said site of said administeredanalgesic by exposing an oxygen activated exothermic medium within theapparatus to a safe, pre-determined amount of oxygen, thus heating theskin proximate said portion of said human body to a safe, pre-determinedtemperature and for a safe, pre-determined amount of time to achievesaid reduced onset time of said analgesic.
 4. A method of treatingbaseline and suddenly increased pain in a human body comprising:administering an analgesic in a sustained release formulation into aportion of said human body to treat a baseline pain within 3 centimeterof a skin surface; applying an apparatus capable of generatingcontrolled heat for a pre-determined duration of time by exposing anoxygen activated exothermic medium within the apparatus to a safe,pre-determined amount of oxygen of the exothermic medium proximate saidinjected, sustained release analgesic at the onset of suddenly increasedpain; and increasing the temperature of skin proximate said portion ofsaid human body to a safe, pre-determined temperature and for a safe,pre-determined amount of time with said apparatus to achieve a desiredincreased concentration of said analgesic in said human body.
 5. Anapparatus capable of heating to a safe, pre-determined temperature rangefor a safe, pre-determined amount of time, said apparatus comprising: ashallow chamber defined by an air impermeable wall having an opening anda cover capable of covering said opening, said covering having a desiredair permeability, and a heat generating medium disposed within saidshallow chamber of said apparatus, said apparatus capable of generatingcontrolled heat by exposing an oxygen activated exothermic medium withinthe apparatus to a safe, pre-determined amount of oxygen.
 6. Acontrolled heat generating apparatus configured to selectively provideheat at a safe, pre-determined temperature and for a safe,pre-determined amount of time, said apparatus comprising: a heating unitcapable of generating heat when supplied with electricity wherein saidheating unit includes a temperature feedback system; and a substantiallytwo-dimensional surface coupled to said heating unit and configured topass said heat to at least one of: (i) a dermal drug delivery system;and (ii) a patient's skin.
 7. In a system that includes a dermal drugdelivery system and a heating unit configured to generate heat whensupplied with electricity for a safe, pre-determined amount of time andbetween a safe, pre-determined temperature range, a method for improvingan administration of a pharmaceutical formulation through a patient'sskin, the method comprising the steps for: using the electrical beatingunit to selectively generate heat; using a two-dimensional surface ofthe electrical heating unit to pass the heat to a receiving surface; andemploying a temperature feedback system to regulate an amount of heatpassed to the receiving surface between a safe, pre-determinedtemperature range and for a safe, pre-determined amount of time.
 8. Anelectrical heating apparatus kit configured to selectively heat apatient's skin in an area associated with a dermal drug delivery system,the kit comprising: a dermal drug delivery system configured toselectively deliver a pre-determined amount of a pharmaceuticalformulation to a patient; and an electrical heat generating unit havinga feedback mechanism to selectively provide heat, regulated between asafe, pre-determined temperature range for a safe, pre-determined amountof time, to at least one of: (i) the dermal drug delivery system; and(ii) the area of the patient's skin associated with the dermal drugdelivery system.
 9. A heating apparatus configured to selectively heat apatient's skin in an area immediately surrounding and under a dermaldrug delivery system, the heating apparatus comprising: a dermal drugdelivery system configured to be selectively placed in contact with apatient's skin and to selectively deliver a pre-determined amount of apharmaceutical formulation through the patient's skin; an infraredgenerating unit coupled to the dermal drug delivery system andconfigured to emit infrared radiation to selectively heat the patient'sskin between a safe, pre-determined temperature range for a safe,pre-determined amount of time; a directing mechanism coupled to theinfrared generating unit and configured to direct the infrared radiationonto at least one of (i) the dermal drug delivery system, and (ii) thepatient's skin; and a temperature feedback mechanism coupled to theinfrared generating unit for regulating the applied heat, wherein thetemperature feedback mechanism includes a temperature sensor.
 10. In asystem that includes a dermal drug delivery system and an infraredgenerating unit, a method for improving an administration of apharmaceutical formulation through a patient's skin, the methodcomprising the steps for: providing the dermal drug delivery system incontact with the patient's skin, wherein the drug delivery systemincludes the pharmaceutical formulation; using the infrared generatingunit to emit infrared radiation to selectively heat the patient's skinbetween a safe, pre-determined temperature range for a safe,pre-determined amount of time in an area immediately surrounding andunder the drug delivery system; using a temperature sensor and feedbackmechanism to provide feedback to the infrared generating unit relatingto a temperature of the pharmaceutical formulation; and using the dermaldrug delivery system to administer the pharmaceutical formulation to thepatient through the patient's skin.
 11. A heating apparatus kitconfigured to selectively heat a patient's skin in an area immediatelysurrounding and under a dermal drug delivery system, the kit comprising:a dermal drug delivery system configured to selectively deliver apre-determined amount of a pharmaceutical formulation to a patient; andan infrared generating unit configured to emit infrared radiation toselectively heat the patient's skin between a safe, pre-determinedtemperature range for a safe, pre-determined amount of time, wherein theinfrared generating unit includes a temperature sensor and feedbackmechanism.